Amidinoindoles, amidinoazoles, and analogs thereof

ABSTRACT

The present application describes amidinoindoles, amidinoazoles, and analogs thereof of formula I: ##STR1## wherein W, W 1 , W 2 , and W 3  are selected from CH and N, provided that one of W 1  and W 2  is C(C(═NH)NH 2 ) and at most two of W, W 1 , W 2 , and W 3  are N and one of J a  and J b  is substituted by --(CH 2 ) n  --Z--A--B, which are useful as inhibitors of factor Xa or thrombin.

This application is a divisional of U.S. application Ser. No. 08/916,736 filed Aug. 18, 1997, now U.S. Pat. No. 5,886,191.

FIELD OF THE INVENTION

This invention relates generally to amidinoindoles, amidinoazoles, and analogs which are inhibitors of trypsin-like serine protease enzymes, especially thrombin and factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.

BACKGROUND OF THE INVENTION

EP 0,540,051 and JP 06227971 describe a series of compounds useful as factor Xa inhibitors or to treat influenza based on the formula: ##STR2## wherein A is an alkylene linker optionally substituted by hydroxyalkyl, carboxyl, alkoxycarbonyl, alkoxycarbonylalkyl, or carboxyalkyl, X is a bond, O, S, or carbonyl, n is 0-4, and Y is an optionally substituted carbocycle or heterocycle. The present invention does not involve compounds containing the above noted combination of A, X, n, and Y.

Tidwell et al, Thrombosis Research 1981, 24, 73-83, describe factor Xa inhibitory activity of a series of aromatic mono- and di-amidines. The amidino aromatic moieties are include indole, indoline, benzofuran and benzimidazole.

Tidwell et al, J. Med. Chem. 1983, 26, 294-298, report a series of amidinoindoles of the formula: ##STR3## wherein one of R¹ and R² is amidine, X may be methyl or ethyl when Y and Z are H, Y may be C(O)CH₂ CH₃ when X and Z are H, and Z may be CHO, COCH₃, COCF₃, or C(O)Ph when X and Y are H. Thrombin inhibition constants are given for these compounds.

EP 0,655,439 discuss IIb/IIIa antagonists of the formula: ##STR4## wherein the core ring is a heterocycle, B is a basic group, A is an acidic group, R₁ is an optional substituent, R₂ is an optional substituent, and L_(a) and L_(b) are linkers which may optionally be substituted. The present invention does not contain the L_(a) -A group.

Fairley et al, J. Med. Chem. 1993, 36, 1746-1753, illustrate a series of bis(amidinobenzimidazoles) and bis(amidinoindoles) of the formulae: ##STR5## wherein R is an amidine or derivative thereof and X is an alkylene, alkenylene, phenylene or phenylenedimethylene linker. The DNA binding capabilities of these compounds were studied and reported, but inhibition of trypsin-like enzymes was not discussed.

WO 95/08540 depicts bis(amidinobenzimidazolyl)alkanes of the formula: ##STR6## wherein Z is an amidine derivative and R and R¹ are selected from a variety of substituents including hydroxyl, amino, and alkoxy. These compounds are said to be useful in the treatment of viruses, specifically HIV. No mention is made of Xa or thrombin inhibition.

Trypsin-like enzymes are a group of proteases which hydrolyzed peptide bonds at basic residues liberating either a C-terminal arginyl or lysyl residue. Among these are enzymes of the blood coagulation and fibrinolytic system required for hemostasis. They are Factors II, X, VII, IX, XII, kallikrein, tissue plasminogen activators, urokinase-like plasminogen activator, and plasmin. Elevated levels of proteolysis by these proteases can result in disease states. For example, consumptive coagulopathy, a condition marked by a decrease in the blood levels of enzymes of both the coagulation system, the fibrinolytic system and accompanying protease inhibitors is often fatal. More specifically, proteolysis by thrombin is required for blood clotting. Inhibition of thrombin results in an effective inhibitor of blood clotting. The importance of an effective inhibitor of thrombin is underscored by the observation that conventional anticoagulants such as heparin (and its complex with the protein inhibitor, antithrombin III) are ineffective in blocking arterial thrombosis associated with myocardial infarctions and other clotting disorders. However, a low molecular weight thrombin inhibitor, containing a different functionality, was effective in blocking arterial thrombosis (Hanson and Harker, Proc. Natl. Acad. Sci. U.S.A. 85, 3184 (1988).

Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca²⁺ and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617-629), inhibition of factor Xa may be more efficient that inactivation of thrombin in interrupting the blood coagulation system.

Therefore, efficacious and specific inhibitors of factor Xa or thrombin are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new thrombin or factor Xa inhibitors.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novel amidinoindoles and analogs thereof which are useful as factor Xa or thrombin inhibitors or pharmaceutically acceptable salts or prodrugs thereof.

It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I): ##STR7## or pharmaceutically acceptable salt or prodrug forms thereof, wherein D, D^(a), J, J^(a), J^(b), W, W¹, W², and W³, are defined below, are effective factor Xa or thrombin inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] Thus, in a first embodiment, the present invention provides a novel compound of formula I: ##STR8## or stereoisomer or pharmaceutically acceptable salt form thereof wherein: W and W³ are selected from CH and N;

W¹ and W² are selected from C, CH, and N;

provided that from 0-2 of W, W¹, W², and W³ are N;

one of D and D^(a) is selected from H, C₁₋₄ alkoxy, CN, C(═NR⁷)NR⁸ R⁹, NHC(═NR⁷)NR⁸ R⁹, NR⁸ CH(═NR⁷), C(O)NR⁸ R⁹, and (CH₂)_(t) NR⁸ R⁹, and the other is absent;

provided that if one of D and D^(a) is H, then at least one of W, W¹, W², and W³ is N;

one of J^(a) and J^(b) is substituted by --(CH₂)_(n) --Z--A--B;

J, J^(a), and J^(b) combine to form an aromatic heterocyclic system containing from 1-2 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹, provided that J^(b) can only be C or N;

J, J^(a), and J^(b) can, alternatively, combine to form a heterocyclic ring wherein J^(b) is N and J and J^(a) are CH₂ substituted with 0-1 R¹ ;

J, J^(a), and J^(b) can, alternatively, combine to form a heterocyclic ring wherein J^(b) is CH, J is NR¹ and J^(a) is CH₂ substituted with 0-1 R¹ ;

R¹ is selected from H, C₁₋₄ alkyl, (CH₂)_(r) OR³, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) C(═O)R², (CH₂)_(r) (CH═CH)(CH₂)_(r) C(═O)R², (CH₂)_(r) NR³ C(═O)R², (CH₂)_(r) SO₂ R⁴, (CH₂)_(r) NR³ SO₂ R⁴, and (CH₂)_(r) -5-membered heterocyclic system having 1-4 heteroatoms selected from N, O, and S;

R² is selected from H, OR³, C₁₋₄ alkyl, NR³ R^(3'), CF₃, and C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶ ;

R³ and R^(3') are independently selected from H, C₁₋₄ alkyl, and C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶ ;

R⁴ is selected from C₁₋₄ alkyl, NR³ R^(3'), and C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶ ;

Z is selected from CH═CH, CH((CH₂)_(m) Q(CH₂)_(m) R⁵), CH((CH₂)_(m) Q(CH₂)_(m) R⁵)C(O)NR³, CH((CH₂)_(m) C(O)(CH₂)_(m) R^(5a)), N((CH₂)_(q) Q(CH₂)_(m) R⁵), N(Q'(CH₂)_(m) R⁵), C(O)N((CH₂)_(m) Q'(CH₂)_(m) R^(5a)), C(O)(CH₂)_(r), C(O)O(CH₂)_(r), OC(O)(CH₂)_(r), C(O)(CH₂)_(r) NR³ (CH₂)_(r), NR³ C(O)(CH₂)_(r), OC(O)NR³ (CH₂)_(r), NR³ C(O)O(CH₂)_(r), NR³ C(O)NR³ (CH₂)_(r), S(O)_(p) (CH₂)_(r), SO₂ CH₂, SCH₂ C(O)NR³, SO₂ NR³ (CH₂)_(r), NR³ SO₂ (CH₂)_(r), and NR³ SO₂ NR³ (CH₂)_(r) ;

Q is selected from a bond, O, NR³, C(O), C(O)NR³, NR³ C(O), SO₂, NR³ SO₂, and SO₂ NR³ ;

Q' is selected from a bond, C(O), C(O)NR³, SO₂, and SO₂ NR³ ;

R⁵ is selected from H, C₁₋₄ alkyl, C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶, provided that when Q is SO₂ or NR³ SO₂, R⁵ is other than H and when Q' is SO₂, R⁵ is other than H;

R^(5a) is selected from NHR₅, OR⁵, and R⁵ ;

A is selected from:

benzyl substituted with 0-2 R⁶,

phenethyl substituted with 0-2 R⁶,

phenyl-CH═ substituted with 0-2 R⁶,

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶, and

5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

B is selected from:

X--Y, C₃₋₆ alkyl, NR³ R^(3'), C(═NR³)NR³ R^(3'), NR³ C(═NR³)NR³ R³ ',

benzyl substituted with 0-2 R⁶,

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶, and

5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

A and B can, alternatively, combine to form a C₉₋₁₀ carbocyclic residue substituted with 0-2 R⁶ or a 9-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

X is selected from C₁₋₄ alkylene, --C(O)--, --C(O)CR³ R^(3') --, --CR³ R^(3') C(O), --S(O)_(p) --, --S(O)_(p) CR³ R^(3') --, --CR³ R^(3') S(O)_(p) --, --S(O)₂ NR³ --, --NR³ S(O)₂ --, --C(O)NR³ --, --NR³ C(O)--, --NR³ --, --NR³ CR³ R^(3') --, --CR³ R^(3') NR³ --, O, --CR³ R^(3') O--, and --OCR³ R^(3') --;

Y is selected from:

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶, and

5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

R⁶ is selected from H, OH, (CH₂)_(n) OR³, halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) C(O)R³, NR³ C(O)R^(3'), NR³ C(O)NR³ R^(3'), CH(═NH)NH₂, NHC(═NH)NH₂, SO₂ NR³ R^(3'), CONHSO₂ R⁴, NR³ SO₂ NR³ R^(3'), NR³ SO₂ --C₁₋₄ alkyl, and (C₁₋₄ alkyl)-tetrazolyl;

R⁷ is selected from H, OH, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl;

R⁸ is selected from H, C₁₋₆ alkyl and (CH₂)_(n) -phenyl;

R⁹ is selected from H, C₁₋₆ alkyl and (CH₂)_(n) -phenyl;

n is selected from 0, 1, 2, 3, and 4;

m is selected from 0, 1, and 2;

p is selected from 0, 1, and 2;

q is selected from 1 and 2; and,

r is selected from 0, 1, 2, 3, and 4;

provided that:

(a) Z is other than CH₂ ; and,

(b) if Z is CH((CH₂)_(m) Q(CH₂)_(m) R⁵) or CH((CH₂)_(m) C(O)(CH₂)_(m) R^(5a)), then B is other than X--Y, a C₃₋₁₀ carbocyclic residue or a 5-10 membered heterocyclic system.

[2] In a preferred embodiment, the present invention provides compounds of formula II: ##STR9## wherein: from 0-1 of W, W¹, W², and W³ are N; R¹ is selected from H, C₁₋₄ alkyl, (CH₂)_(r) OR³, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) C(═O)R², (CH₂)_(r) NR³ C(═O)R², (CH₂)_(r) SO₂ R⁴, (CH₂)_(r) NR³ SO₂ R⁴, and (CH₂)_(r) -5-membered heterocyclic system having 1-4 heteroatoms selected from N, O, and S;

R² is selected from H, OR³, C₁₋₄ alkyl, NR³ R^(3'), and CF₃ ;

R³ and R^(3') are independently selected from H, C₁₋₄ alkyl, and phenyl;

R⁴ is selected from C₁₋₄ alkyl, phenyl and NR³ R^(3') ;

Z is selected from CH═CH, CH((CH₂)_(m) Q(CH₂)_(m) R⁵), CH((CH₂)_(m) Q(CH₂)_(m) R⁵)C(O)NR³, CH((CH₂)_(m) C(O)(CH₂)_(m) R^(5a)), N((CH₂)_(q) Q(CH₂)_(m) R⁵), N(Q'(CH₂)_(m) R⁵), C(O)N((CH₂)_(m) Q'(CH₂)_(m) R^(5a)), C(O), C(O) CH₂, C(O) 0, OC(O), C(O)(CH₂)_(r) NR³ (CH₂)_(r), NR³ C(O), OC(O)NR³, NR³ C(O)O, NR³ C(O)NR³, S(O)_(p), SO₂ CH₂, SO₂ NR³, NR³ SO₂, and NR³ SO₂ NR³ ;

B is selected from:

X--Y, C₃₋₆ alkyl,

benzyl substituted with 0-2 R⁶,

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶, and

5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

A and B can, alternatively, combine to form a C₉₋₁₀ carbocyclic residue substituted with 0-2 R⁶ or a 9-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ; and,

R⁶ is selected from H, OH, (CH₂)_(n) OR³, halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) C(O)R³, NR³ C(O)R^(3'), NR³ C(O)NR³ R^(3'), SO₂ NR³ R^(3'), CONHSO₂ R⁴, NR³ SO₂ NR³ R^(3'), NR³ SO₂ --C₁₋₄ alkyl and (C₁₋₄ alkyl)-tetrazolyl.

[3] In a more preferred embodiment, the present invention provides compounds of formula II, wherein:

J, J^(a), and J^(b) combine to form an aromatic heterocyclic system containing from 1-2 nitrogen atoms, substituted with 0-1 R¹ ;

J, J^(a), and J^(b) can, alternatively, combine to form a heterocyclic ring wherein J^(b) is N and J and J^(a) are CH₂ substituted with 0-1 R¹ ;

J, J^(a), and J^(b) can, alternatively, combine to form a heterocyclic ring wherein J^(b) is CH, J is NR¹ and J^(a) is CH₂ substituted with 0-1 R¹ ;

R¹ is selected from H, C₁₋₄ alkyl, (CH₂)_(r) OR³, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) C(═O)R², (CH₂)_(r) NR³ C(═O)R², (CH₂)_(r) SO₂ R⁴, and (CH₂)_(r) NR³ SO₂ R⁴ ;

Z is selected from CH((CH₂)_(m) Q(CH₂)_(m) R⁵), CH((CH₂)_(m) Q(CH₂)_(m) R⁵)C(O)NR³, CH((CH₂)_(m) C(O)(CH₂)_(m) R^(5a)), N((CH₂)_(q) Q(CH₂)_(m) R⁵), N(Q'(CH₂)_(m) R⁵), C(O)N((CH₂)_(m) Q'(CH₂)_(m) R^(5a)), C(O), C(O) CH₂, C(O)(CH₂)_(r) NR³ (CH₂)_(r), NR³ C(O), NR³ C(O)NR³, S(O)₂, SO₂ CH₂, SO₂ NR³, NR³ SO₂, and NR³ SO₂ NR³ ;

A is selected from:

benzyl substituted with 0-2 R⁶,

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶, and

5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

B is selected from:

X--Y, C₃₋₆ alkyl,

benzyl substituted with 0-2 R⁶,

C₅₋₆ carbocyclic residue substituted with 0-2 R⁶, and

5-6 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

X is selected from --C(O)--, --C(O)CR³ R^(3') --, --S(O)₂ --, --S(O)_(p) CR³ R^(3') --, --S(O)₂ NR³ --, --C(O)NR³ --, --NR³ --, --NR³ CR³ R^(3') --, and O;

Y is selected from:

C₅₋₆ carbocyclic residue substituted with 0-2 R⁶, and

5-6 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

R⁶ is selected from H, OH, (CH₂)_(n) OR³, halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r) N³ R^(3'), (CH₂)_(r) C(O)R³, NR³ C(O)R^(3'), NR³ C(O)NR³ R^(3'), SO₂ NR³ R^(3'), CONHSO₂ R⁴, NR³ SO₂ NR³ R^(3'), NR³ SO₂ --C₁₋₄ alkyl and (C₁₋₄ alkyl)-tetrazolyl;

n is selected from 0, 1, and 2; and,

r is selected from 0, 1, and 2.

[4] In an even more preferred embodiment, the present invention provides compounds of formula II: ##STR10## wherein: J and J^(b) combine to form an aromatic heterocyclic system containing from 1-2 nitrogen atoms, substituted with 0-1 R¹ ;

J and J^(b) can, alternatively, form a heterocyclic ring wherein J^(b) is N and J is CH₂ substituted with 0-1 R¹ ;

J and J^(b) can, alternatively, form a heterocyclic ring wherein J^(b) is CH and J is NR¹ ;

Z is selected from C(O)N(Q'R^(5a)), C(O), C(O)NR³, NR³ C(O), and SO₂ NR³ ;

Q' is selected from C(O) and C(O)NR³ ;

R⁵ is selected from H and C₁₋₄ alkyl;

R^(5a) is selected from NHR⁵, OR⁵, and R⁵ ;

A is selected from:

benzyl substituted with 0-1 R⁶,

phenyl substituted with 0-1 R⁶,

piperidinyl substituted with 0-1 R⁶,

piperazinyl substituted with 0-1 R⁶, and

pyridyl substituted with 0-1 R⁶ ;

B is selected from:

X--Y,

benzyl substituted with 0-1 R⁶,

phenyl substituted with 0-2 R⁶,

cyclohexyl substituted with 0-1 R⁶, and

pyridyl substituted with 0-1 R⁶ ;

X is selected from: --C(O)--, --S(O)₂ --, SO₂ CH₂, --S(O)₂ NR³ --, --NR³ -- and --C(O)NR³ --;

Y is selected from:

phenyl substituted with 0-2 R⁶, and

pyridyl substituted with 0-1 R⁶ ;

R⁶ is selected from H, OH, (CH₂)_(n) OR³, halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) C(O)R³, NR³ C(O)R^(3'), NR³ C(O)NR³ R^(3'), SO₂ NR³ R^(3'), CONHSO₂ R⁴, NR³ SO₂ NR³ R^(3'), NR³ SO₂ --C₁₋₄ alkyl and (C₁₋₄ alkyl)-tetrazolyl;

n is selected from 0, 1, and 2.

[5] In a further preferred embodiment, the present invention provides compounds of formula IV: ##STR11## wherein A, B, D, and Z are as defined above.

[6] In a still further preferred embodiment, the present invention provides compounds selected from:

3-((4-cyclohexyl)phenylaminomethylcarbonyl)methyl-5-amidinoindole

3-(4-p-toluenesulfonyl-piperazinecarbonyl)methyl-5-amidinoindole

3-(4-(2-aminosulfonylphenyl)pyridine-2-aminocarbonyl)methyl-5-amidinoindole;

3-(4-[2-tetrazole]phenyl)phenylaminocarbonyl)methyl-5-amidinoindole;

3-(4-biphenylaminocarbonyl)methyl-5-amidinoindole;

3-(4-(phenylmethylsulfonyl)piperazinecarbonyl)methyl-5-amidinoindole;

3-(4-cyclohexylphenylaminocarbonyl)methyl-5-amidinoindole;

3-(4-benzylpiperazinecarbonyl)methyl-5-amidinoindole;

3-(3-amidinobenzylamino(methylcarbonylmethoxy)carbonyl)methyl-5-amidinoindole;

3-(4-(2-aminosulfonyl)phenyl)phenylaminocarbonylmethyl-5-amidinoindole;

3-(1-benzylpiperidine-4-aminocarbonyl)methyl-5-amidinoindole;

3-(4-phenylpiperazinecarbonyl)methyl-5-amidinoindole;

3-(4-benzylpiperidinecarbonyl)methyl-5-amidinoindole;

3-{2-bromo-4-(2-aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-cyanoindole;

3-{2-methyl-4-(2-aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-methylamino indole;

3-{2-fluoro-4-(2-aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-amidnoindole;

3-{2-chloro-4-(2-aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-cyanoindole;

3-{2-iodo-4-(2-aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-cyanoindole;

3-{2-methyl-4-(2-aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-amidinoindole;

3-{2-methyl-4-(2-(t-butylaminosulfonyl))phenylphenylaminocarbonyl)methyl-5-amidinoindole;

3-{4-(2-aminosulfonyl)phenyl)phenylaminocarbonylmethyl-α-(methylcarboxy methyl ether)-5-amidinoindole;

3-{4-(2-aminosulfonyl)phenyl)phenylaminocarbonylmethyl-α-(benzyl)-5-amidinoindole;

3-{4-(2-trifluoromethyl)phenyl)pyrid-2-ylaminocarbonylmethyl-5-amidinoindole;

3-{4-(2-ethylaminosulfonyl)phenyl)phenylaminocarbonylmethyl-5-amidinoindole;

3-{4-(2-propylaminosulfonyl)phenyl)phenyl}aminocarbonylmethyl-5-amidinoindole;

2-methyl-3-{2-iodo-4-(2-aminosulfonyl)phenyl)phenyl}aminocarbonylmethyl-5-amidinoindole;

2-methyl-3-{4-(2-aminosulfonyl)phenyl)phenyl}aminocarbonylmethyl-5-amidinoindole;

3-{4-(2-aminosulfonyl)phenyl)phenyl}-N-methylaminocarbonylmethyl-5-amidinoindole;

2-methyl-3-{4-(2-t-butylaminosulfonyl)phenyl)phenyl}aminocarbonylmethyl-5-methoxyindole; and,

3-{4-(2-N-methylaminosulfonyl)phenyl)phenyl}-N-methylaminocarbonylmethyl-5-amidinoindole;

or a stereoisomer or pharmaceutically acceptable salt form thereof.

[7] In another further preferred embodiment, the present invention provides compounds of formula IVa: ##STR12## wherein A, B, D, and Z are as defined above.

[8] In another still further preferred embodiment, the present invention provides compounds selected from:

3-{4-(2-(n-butylaminosulfonyl)phenylphenylaminocarbonyl)methyl-5-cyanoindoline;

3-{4-(2-(n-propylaminosulfonyl)phenylphenylaminocarbonyl)methyl-5-amidinoindoline;

(-)-3-{4-(2-aminosulfonyl)phenyl)pyrid-2-ylaminocarbonylmethyl-5-amidinoindoline;

3-{4-(2-aminosulfonyl)phenyl)pyrid-2-ylaminocarbonylmethyl-5-amidinoindoline;

3-{4-(2-dimethylaminosulfonyl)phenyl)phenylaminocarbonylmethyl-5-amidinoindoline;

(+)-3-{4-(2-t-butylaminosulfonyl)phenyl)pyrid-2-ylaminocarbonylmethyl-5-amidinoindoline;

(-)-3-{4-(2-t-butylaminosulfonyl)phenyl)pyrid-2-ylaminocarbonylmethyl-5-amidinoindoline;

3-{4-(2-aminosulfonyl)phenyl)pyrid-2-yl)aminocarbonylmethyl-5-aminocarboxyindoline;

3-{4-(2-t-butylaminosulfonyl)phenyl)phenyl}aminocarbonylmethyl-5-amidinoindoline; and,

3-{4-(2-t-butylaminosulfonyl)phenyl)pyrid-2-yl}aminocarbonylmethyl-5-amidinoindoline;

or a stereoisomer or pharmaceutically acceptable salt form thereof.

[9] In another further preferred embodiment, the present invention provides compounds of formula IVb: ##STR13## wherein A, B, D, and Z are as defined above.

[10] In another still further preferred embodiment, the present invention provides compounds selected from:

3-{4-(2-aminosulfonyl)phenyl)pyrid-2-ylaminocarbonylmethyl-6-amidinoindazole;

3-{4-(2-aminosulfonyl)phenyl)phenyl aminocarbonylmethyl-6-amidinoindazole;

3-{4-(2-t-butyl aminosulfonyl)phenyl)pyrid-2-ylaminocarbonylmethyl-6-amidinoindazole; and,

3-{4-(2-t-butylaminosulfonyl)phenyl)phenyl aminocarbonylmethyl-6-amidinoindazole;

or a stereoisomer or pharmaceutically acceptable salt form thereof.

[11] In another further preferred embodiment, the present invention provides compounds of formula IVc: ##STR14## wherein D, Da, Z, A, and B are as defined above.

[12] In another still further preferred embodiment, the present invention provides compounds selected from:

[4-(phenyl)phenylcarbonyl]methyl-6-amidinobenzimidazole;

[4-(phenyl)phenylcarbonyl]methyl-5-amidinobenzimidazole;

[4-(3-aminophenyl)phenylcarbonyl]methyl-6-amidinobenzimidazole;

[4-(3-aminophenyl)phenylcarbonyl]methyl-5-amidinobenzimidazole;

[4-(4-fluorophenyl)phenylcarbonyl]methyl-6-amidinobenzimidazole;

[4-(4-formylphenyl)phenylcarbonyl]methyl-6-amidinobenzimidazole;

[4-(2-aminosulfonylphenyl)phenylcarbonyl]methyl-6-amidinobenzimidazole;

[4-(2-tert-butylaminosulfonylphenyl)phenylcarbonyl]methyl-6-amidinobenzimidazole;

{4-[(2-tetrazolyl)phenyl]phenylcarbonyl}methyl-6-amidinobenzimidazole;

[4-(2-aminosulfonylphenyl)phenylaminocarbonyl]methyl-6-amidinobenzimidazole;

[4-(2-aminosulfonylphenyl)phenylaminocarbonyl]methyl-5-amidinobenzimidazole;

1-(4-benzylpiperidinecarbonyl)methyl-6-amidinobenzimidazole;

1-(4-benzylpiperidinecarbonyl)methyl-5-amidinobenzimidazole;

1-(4-benzylpiperidinecarbonyl)methyl-6-amidinobenzimidazole;

2-[4-(2-aminosulfonylphenyl)phenylcarbonyl]methyl-6-amidinobenzimidazole;

2-[4-(2-tert-butylaminosulfonylphenyl)phenylcarbonyl]methyl-5-azabenzimidazole;

2S-[4-(2-tert-aminosulfonylphenyl)phenylaminocarbonyl]methyl-thio-1H-imidazo(4,5-C) pyridine; and,

2S-[4-(2-aminosulfonylphenyl)phenylaminocarbonyl]methyl-thio-1H-imidazo(4,5-C) pyridine;

or a stereoisomer or pharmaceutically acceptable salt form thereof.

[13] In a preferred embodiment, the present invention provides compounds of formula V: ##STR15## wherein one of R and R^(a) is --(CH₂)_(n) --Z--A--B and the other H;

W, W², and W³ are selected from CH and N, provided that at most one of W, W², and W³ can be N;

J is selected from N and C--R¹ ;

R¹ is selected from H, O, (CH₂)_(r) OR³, (CH₂)_(r) C(═O)R², (CH═CH)C(═O)R², (CH₂)_(r) NR³ C(═O)R², (CH₂)_(r) SO₂ R⁴, (CH₂)_(r) NR³ SO₂ R⁴, and (CH₂)_(r) -5-membered heterocyclic system having 1-4 heteroatoms selected from N, O, and S;

R² is selected from H, OR³, C₁₋₄ alkyl, NR³ R^(3'), CF₃, and C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶ ;

R³ and R^(3') are independently selected from H, C₁₋₄ alkyl, and C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶ ;

R⁴ is selected from OR³, C₁₋₄ alkyl, NR³ R^(3'), and C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶ ;

Z is selected from CH═CH, CH(CH₂)_(m) Q(CH₂)_(m) R⁵, CH((CH₂)_(m) Q(CH₂)_(m) R⁵)C(O)NR³, CH(CH₂)_(m) C(O)(CH₂)_(m) R^(5a), N(CH₂)_(q) Q(CH₂)_(m) R⁵, NQ'(CH₂)_(m) R⁵, C(O)N((CH₂)_(m) Q'(CH₂)_(m) R^(5a)), C(O), C(O)CH₂, C(O)O, OC(O), C(O)NR³ (CH₂)_(r), NR³ C(O), OC(O)NR³, NR³ C(O)O, NR³ C(O)NR³, S(O)_(p), SO₂ CH₂, SO₂ NR³, NR³ SO₂, and NR³ SO₂ NR³ ;

Q is selected from a bond, O, NR³, C(O), C(O)NR³, NR³ C(O), SO₂, NR³ SO₂, and SO₂ NR³ ;

Q' is selected from a bond, C(O), C(O)NR³, SO₂, and SO₂ NR³ ;

R⁵ is selected from H, C₁₋₄ alkyl, C₃₋₈ carbocyclic residue substituted with 0-2 R⁶, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶, provided that when Q is SO₂ or NR³ SO₂, R⁵ is other than H and when Q' is SO₂, R⁵ is other than H;

R^(5a) is selected from NHR₅, OR⁵, and R⁵ ;

A is selected from:

benzyl substituted with 0-2 R⁶,

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶, and

5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

B is selected from:

H, X--Y NR³ R³, C(═NR³)NR³ R^(3'), NR³ C(═NR³)NR³ R^(3'),

benzyl substituted with 0-2 R⁶,

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶, and

5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

X is selected from C₁₋₄ alkylene, --C(O)--, --C(O)CR³ R^(3') --, --CR³ R^(3') C(O), --S(O)_(p) --, --S(O)_(p) CR³ R^(3') --, --CR³ R^(3') S(O)_(p) --, --S(O)₂ NR³ --, --NR³ S(O)₂ --, --C(O)NR³ --, --NR³ C(O)--, --NR³ --, --NR³ CR³ R^(3') --, --CR³ R^(3') NR³ --, O, --CR³ R^(3') --, and --OCR³ R^(3') --;

Y is selected from:

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶, and

5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

R⁶ is selected from H, OH, (CH₂)_(n) OR³, halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) C(O)R³, NR³ C(O)R^(3'), NR³ C(O)NR³ R^(3'), CH(═NH)NH₂, NHC(═NH)NH₂, C(═O)R³, SO₂ NR³ R^(3'), NR³ SO₂ NR³ R^(3'), and NR³ SO₂ --C₁₋₄ alkyl;

n is selected from 0, 1, 2, 3, and 4;

m is selected from 0, 1, and 2;

p is selected from 0, 1, and 2;

q is selected from 1 and 2; and,

r is selected from 0, 1, 2, 3, and 4.

[14] In another more preferred embodiment, the present invention provides compounds of formula VI: ##STR16## wherein one of R and R^(a) is --(CH₂)_(n) --Z--A--B and the other H;

W and W² are selected from CH and N, provided that at most one of W and W² can be N;

J is selected from N and C--R¹ ;

R¹ is selected from H, (CH₂)_(r) OR³, (CH₂)_(r) C(═O)R², (CH₂)_(r) NR³ C(═O)R², (CH═CH)C(═O)R², (CH₂)_(r) SO₂ R⁴, and (CH₂)_(r) NR³ SO₂ R⁴ ;

R² is selected from H, OR³, C₁₋₄ alkyl, NR³ R^(3'), and CF₃ ;

R³ and R^(3') are independently selected from H, C₁₋₄ alkyl, and phenyl;

R⁴ is selected from OR³, C₁₋₄ alkyl, NR³ R^(3'), and phenyl;

Z is selected from C(O), C(O)CH₂, C(O)NR³, NR³ C(O), S(O)₂, SO₂ CH₂, SO₂ NR³, NR³ SO₂, and NR³ SO₂ NR³ ;

A is selected from:

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶, and

5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

B is selected from:

X--Y,

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶, and

5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

X is selected from --C(O)--, --C(O)CR³ R^(3') --, --CR³ R^(3') C(O), --S(O)_(p) --, --S(O)_(p) CR³ R^(3') --, --CR³ R^(3') S(O)_(p) --, --S(O)₂ NR³ --, --NR³ S(O)₂ --, --C(O)NR³ --, --NR³ --, --NR³ CR³ R^(3') --, and --CR³ R^(3') NR³ --;

Y is selected from:

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶, and

5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

R⁶ is selected from H, OH, (CH₂)_(n) OR³, halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) C(O)R³, NR³ C(O)R^(3'), NR³ C(O)NR³ R^(3'), C(═O)R³, SO₂ NR³ R^(3'), NR³ SO₂ NR³ R^(3'), and NR³ SO₂ --C₁₋₄ alkyl;

n is selected from 0, 1, 2, 3, and 4;

p is selected from 0, 1, and 2; and,

r is selected from 0, 1, 2, 3, and 4.

[15] In another even more preferred embodiment, the present invention provides compounds of formula VII: ##STR17## wherein, W and W² are selected from CH and N, provided that at most one of W and W² can be N;

R¹ is selected from H, (CH₂)_(r) OR³, (CH₂)_(r) C(═O)R², (CH₂)_(r) NR³ C(═O)R², (CH═CH)C(═O)R², (CH₂)_(r) SO₂ R⁴, and (CH₂)_(r) NR³ SO₂ R⁴ ;

R² is selected from H, OR³, C₁₋₄ alkyl, NR³ R^(3'), and CF₃ ;

R³ and R^(3') are independently selected from H, C₁₋₄ alkyl, and phenyl;

R⁴ is selected from OR³, C₁₋₄ alkyl, NR³ R^(3'), and phenyl;

Z is selected from C(O), C(O)CH₂, C(O)NR³, S(O)₂, SO₂ CH₂, SO₂ NR³, and NR³ SO₂ NR³ ;

A is selected from:

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶, and

5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

B is selected from:

X--Y,

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶, and

5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

X is selected from --S(O)_(p) --, --S(O)_(p) CR³ R^(3') --, --CR³ R³ 'S(O)_(p) --, --S(O)₂ NR³ --, --NR³ S(O)₂ --, and --C(O)NR³ --;

Y is selected from:

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁶, and

5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ;

R⁶ is selected from H, OH, (CH₂)_(n) OR³, halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) C(O)R³, NR³ C(O)R^(3'), NR³ C(O)NR³ R^(3'), C(═O)R³, SO₂ NR³ R^(3'), NR³ SO₂ NR³ R^(3'), and NR³ SO₂ --C₁₋₄ alkyl;

n is selected from 0, 1, 2, 3, and 4;

p is selected from 0, 1, and 2; and,

r is selected from 0, 1, 2, 3, and 4.

[16] In another further preferred embodiment, the present invention provides compounds selected from:

1-(4-benzylpiperidinecarbonyl)methyl-5-amidinoindole;

1-(4-benzylpiperidinecarbonyl)ethyl-5-amidinoindole;

1-(4-(3-fluoro)benzylpiperidinecarbonyl)methyl-5-amidinoindole;

1-(1-(4-amidino)benzyl-N-(methylacetate)aminocarbonyl)methyl-5-amidinoindole;

methyl 1-(4-benzylpiperidinecarbonyl)methyl-5-amidinoindole-3-propanoate;

1-((4-benzylpiperidinecarbonyl)methyl-(3-ethanehydroxyl)-5-amidinoindole;

1-(4-benzylpiperidine-l-carbonyl)methyl-3-methylcarboxylic acid-5-amidinoindole;

1-(1-benzylpiperidine-4-aminocarbonyl)methyl-5-amidinoindole;

1-(4-benzoylpiperidinecarbonyl)methyl-5-amidinoindole;

1-(4-(3-fluoro)benzylpiperazinecarbonyl)methyl-5-amidinoindole;

1-(4-phenylbenzylaminocarbonyl)methyl-5-amidinoindole;

methyl 1-(4-benzylpiperidinecarbonyl)methyl-5-amidinoindole-3-propenoate; and,

1-(4-(2-fluoro)benzylpiperidinecarbonyl)methyl-5-amidinoindole;

or a stereoisomer or pharmaceutically acceptable salt form thereof.

In a second embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug form thereof.

In a third embodiment, the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug form thereof.

DEFINITIONS

The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.

When any variable (e.g., R⁶) occurs more than one time in any constituent or formula for a compound, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R⁶, then said group may optionally be substituted with up to two R⁶ and R⁶ at each occurrence is selected independently from the defined list of possible R⁶. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, "C₁₋₄ alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl; "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like.

"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, and iodo; and "counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.

As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,; [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term "heterocycle" or "heterocyclic system" is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another.

As used herein, the term "aromatic heterocyclic system" is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl., oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, thianthrenyl, thiazolyl, thienyl, thienothiazole, thienooxazole, thienoimidazole, thiophenyl, triazinyl, xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

When a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term "substituted", as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

"Prodrugs" are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like. Preferred prodrugs are amidine prodrugs wherein either D or D^(a) is C(═NH)N(H)R¹⁰, and R¹⁰ is selected from OH, C₁₋₄ alkoxy, C₆₋₁₀ aryloxy, C₁₋₄ alkoxycarbonyl, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, and C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl. More preferred prodrugs are where R⁷ is OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, and methylcarbonyloxymethoxycarbonyl.

"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

SYNTHESIS

Compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those methods described below. Each of the references cited below are hereby incorporated herein by reference. All the temperatures are reported herein in degrees Celsius.

The compounds of Formula I can be prepared using the reactions and techniques described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).

The following descriptions detail general methods of making benzimidazoles, indazoles and indoles through a variety of intermediates. These methods are not intended to represent all of the possible means of making the above compounds, merely a broad representation. One of ordinary skill in the art would readily understand what starting groups would be necessary to make all of the present compounds.

Intermediate 1 which can be formed via acylation of 4-amino-3-nitrobenzonitrile (Aldrich Chemical Co.) with an acyl chloride (R¹ CHO) or an anhydride ((R¹ CO)₂ O) in the presence of a base, followed by hydrogenation is shown below in Scheme 1. Reductive amination of an aldehyde (RCHO) in the presence of 1 using borane-pyridine in acetic acid can afford N-alkylated product 2. Alkylation of 1 with a halide (P₃ X) in the presence of a base, such as Cs₂ CO₃, can provide compound 3. Compounds 2 and 3 can be subjected to the Pinner reaction to give 6-amidino-benzimidazole derivative 4 and 5-amidino-benzimidazole derivative 5, respectively (see Khanna et al J. Org. Chem. 1995, 60, 960). ##STR18##

Scheme 2 shows palladium (0) catalyzed coupling of 3-amino-4-nitrophenyl halides with zinc cyanide in DMF under reflux can provide compound 6 (see Lawton et al J. Org. Chem. 1959, 24, 26). Acylation of 6 with an acyl chloride or anhydride in the presence of base, followed by hydrogenation can form compound 7. Alkylation of 7 with a halide in the presence of a base, such as Cs₂ CO₃, can provide compound 8. Reductive amination of an aldehyde with 7 using borane-pyridine in acetic acid can afford N-alkylated product 9. Compounds 8 and 9 can be converted to either their 6-amidino-benzimidazole or 5-amidino-benzimidazole derivatives, respectively via the Pinner reaction. ##STR19##

Ullmann reaction of 4-chloro-3-nitrobenzonitrile with an amine (P₃ NH₂) in the presence of a base, such as NaHCO₃, can form compound 10 shown in Scheme 3. Hydrogenation of 10, followed by cyclization with an acid, such as formic acid, can give compound 5, which can be converted to its 5-amidino-benzimidazole derivatives as described above. In addition, compound 5 could be derivatized by addition of Br--(CH₂)_(n) --Z--A--B and the resulting mixture subjected to the Pinner reaction and separated by standard techniques. ##STR20##

As described in Scheme 4, bromination of 4-aminobenzonitrile with NBS, followed by treatment with NaNO₂ and Cu₂ O in conc. HCl can provide compound 11 (see Tsuji et al Chem. Pharm. Bull. 1992, 40, 2399). Ullmann reaction of 11 with an amine in the presence of a base, such as NaHCO₃, can form compound 12. Hydrogenation of 11, followed by cyclization with formic acid can give compound 8, which can be converted to its 6-amidino-benzimidazole derivative as described above. ##STR21##

Scheme 5 details the synthesis of 2-substituted-amidino-benzimidazoles from 3,4-diamino-benzonitrile and 3-amino-4-hydroxybenzonitrile 13 which are obtained by hydrogenation of 4-amino-3-nitro-benzonitrile or 4-hydroxy-3-nitrobenzonitrile. Treatment of 13 with an acyl chloride or an acid in the presence of PPA can form compound 14 (see Walker et al Synthesis 1981, 303). Compound 14 can be converted to its amidino derivative via the Pinner reaction. Alternatively, when Y is NH, alkylation of 14 with a halide in the presence of a base, such as K₂ CO₃, can afford a mixture of two regioisomers 15 and 16, which can, after being separated, be subjected to the Pinner reaction to give 2-substituted-6-amidino-benzimidazoles and 2-substituted-5-amidino-benzimidazole derivatives, respectively. ##STR22##

Protection of 6-hydroxy-indazole with pivalic anhydride in the presence of a base, followed by treatment with triflic anhydride can give compound 17 as shown in Scheme 6. Palladium (0) catalyzed coupling of 17 with zinc cyanide can provide compound 18. Deprotection of compound 18 under acidic conditions, followed by alkylation of with a halide in the presence of a base can yield compound 19, which can be converted to its 6-amidino-indazole derivative via the Pinner reaction. ##STR23##

1-Substituted-amidino-indoles and -indazoles could be made from 5-cyanoindole as outlined below in Scheme 7. Intermediate 21 can easily be obtained via alkylation of 20 with Br(CH₂)_(n) Z. Peptide coupling with H--A--B using the BOP reagent or alkylation should afford intermediate 22 which is can then be converted to amidine 23 under Pinner conditions. ##STR24##

Scheme 8 shows 3-substituted-amidino-indoles and -indazoles are also derivable from 5-cyanoindole. Compound 26 may be obtained by substitution of R¹ on 24 to form 25 and acylation of 25 in the presence of oxalyl chloride at r.t. under nitrogen atmosphere. The compound can be subjected to selective ketone reduction with triethylsilane in trifluoroacetic acid for 3 h and then coupled with H--A--B. ##STR25##

The piperazine phenylsulfonamide, 31, and various other sulfonamide analogues can be prepared from commercially available BOC-piperazine via sulfonation with phenylsulfonyl chloride in CH₂ Cl₂ and triethylamine as indicated in Scheme 9. ##STR26##

Biphenyl compounds may be prepared by procedures known to those of skill in the art. For example, Scheme 10 shows how to obtain substituted biphenyls via a Suzuki coupling with BOC protected 4-bromoaniline (or 1-bromo-4-nitrobenzene) to afford compound 35. ##STR27##

Compound 38 can be obtained via deprotection of the t-butyl group when R⁶ ═SO₂ NH--t--Bu, with TFA followed by alkylation or acylation with R³ X as outlined in Scheme 11. ##STR28##

Scheme 12 shows how intermediates 43-45 may be obtained via the same intermediate 39. Acylation with oxalyl chloride followed by addition of methanol should yield ketoester 40 and selective reduction with triethyl silane may afford methyl acetate 42. Reduction with sodium borohydride can give the alcohol which then can be converted to 45 with R³ X. Intermediate 43 may be obtained via formylation with POCl₃ in DMF to yield aldehyde 41 which could then subjected to a Wittig olefination to afford compound 43. ##STR29##

Sulfonyl chloride 49 may be obtained via aldehyde 47. The aldehyde can be reduced with sodium borohydride, sulfonated with methane sulfonyl chloride, and displaced with sodium sulfite in ethanol. Sulfonyl chloride 49 should then be obtained via chlorination with sulfonyl chloride as detailed in Scheme 13. ##STR30##

Scheme 14 details how substitution at the 2-position of the indole may be acomplished via lithiation with s-BuLi at -78° C. followed by addition of R¹ X to yield compound 51. Compound 51 can then converted to compound 52 by the previously mentioned methodology. ##STR31##

In Scheme 15, it is shown how the 5-cyanoindole compound 54 may be prepared via compound 53 by using sodium methoxide in the presence of nitromethane, followed by Zn reduction and condensation. ##STR32##

Groups A and B are available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practioners skilled in the art of organic synthesis. The required reactive functional groups appended to analogs of A and B are also available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practioners skilled in the art of organic synthesis. In the tables that follow the chemistry required to effect the coupling of A to B is outlined.

                                      TABLE 1                                      __________________________________________________________________________     Preparation of Amide, Ester, Urea, Sulfonamide and                               Sulfamide linkages between A and B.                                                       then the reactive                                                                         to give the                                              Rxn. if A substituent of following product                                     No. contains : Y is : A--X--Y :                                              __________________________________________________________________________     1  A--NHR.sup.3 as a                                                                        ClC(O)--Y  A--NR.sup.3 --C(O)--Y                                     substituent                                                                   2 a secondary NH ClC(O)--Y A--C(O)--Y                                           as part of a                                                                   ring or chain                                                                 3 A--OH as a ClC(O)--Y A--O--C(O)--Y                                            substituent                                                                   4 A--NHR.sup.3 as a ClC(O)--CR.sup.3 R.sup.3' --Y A--NR.sup.3 --C(O)--CR                             .sup.3 R.sup.3' --Y                                       substituent                                                                   5 a secondary NH ClC(O)--CR.sup.3 R.sup.3' --Y A--C(O)--CR.sup.3                                     R.sup.3' --Y                                              as part of a                                                                   ring or chain                                                                 6 A--OH as a ClC(O)--CR.sup.3 R.sup.3' --Y A--O--C(O)--CR.sup.3                                      R.sup.3' --Y                                              substituent                                                                   7 A--NHR.sup.3 as a ClC(O)NR.sup.3 --Y A--NR.sup.3 --C(O)NR.sup.3 --Y                                  substituent                                            8 a secondary NH ClC(O)NR.sup.3 --Y A--C(O)NR.sup.3 --Y                         as part of a                                                                   ring or chain                                                                 9 A--OH as a ClC(O)NR.sup.3 --Y A--O--C(O)NR.sup.3 --Y                          substituent                                                                   10 A--NHR.sup.3 as a ClSO.sub.2 --Y A--NR.sup.3 --SO.sub.2 --Y                  substituent                                                                   11 a secondary NH ClSO.sub.2 --Y A--SO.sub.2 --Y                                as part of a                                                                   ring or chain                                                                 12 A--NHR.sup.3 as a ClSO.sub.2 --CR.sup.3 R.sup.3' --Y A--NR.sup.3                                  --SO.sub.2 --CR.sup.3 R.sup.3' --Y                        substituent                                                                   13 a secondary NH ClSO.sub.2 --CR.sup.3 R.sup.3' --Y A--SO.sub.2                                     --CR.sup.3 R.sup.3' --Y                                   as part of a                                                                   ring or chain                                                                 14 A--NHR.sup.3 as a ClSO.sub.2 --NR.sup.3 --Y A--NR.sup.3 --SO.sub.2                                --NR.sup.3 --Y                                            substituent                                                                   15 a secondary NH ClSO.sub.2 --NR.sup.3 --Y A--SO.sub.2 --NR.sup.3 --Y                                 as part of a                                            ring or chain                                                                 16 A--C(O)Cl HO--Y as a A--C(O)--O--Y                                            substituent                                                                  17 A--C(O)Cl NHR.sup.3 --Y as a A--C(O)--NR.sup.3 --Y                            substituent                                                                  18 A--C(O)Cl a secondary NH as A--C(O)--Y                                        part of a ring or                                                              chain                                                                        19 A--CR.sup.3 R.sup.3' C(O)Cl HO--Y as a A--CR.sup.3 R.sup.3' C(O)--O--                             Y                                                          substituent                                                                  20 A--CR.sup.3 R.sup.3' C(O)Cl NHR.sup.3 --Y as a A--CR.sup.3 R.sup.3'                               C(O)--NR.sup.3 --Y                                         substituent                                                                  21 A--CR.sup.3 R.sup.3' C(O)Cl a secondary NH as A--C(R.sup.3).sub.2                                 C(O)--Y                                                    part of a ring or                                                              chain                                                                        22 A--SO.sub.2 Cl NHR.sup.3 --Y as a A--SO.sub.2 --NR.sup.3 --Y                                         substituent                                           23 A--SO.sub.2 Cl a secondary NH as A--SO.sub.2 --Y                              part of a ring or                                                              chain                                                                        24 A--CR.sup.3 R.sup.3' SO.sub.2 Cl NHR.sup.3 --Y as a A--CR.sup.3                                   R.sup.3' SO.sub.2 --NR.sup.3 --Y                           substituent                                                                  25 A--CR.sup.3 R.sup.3' SO.sub.2 Cl a secondary NH as A--CR.sup.3                                    R.sup.3' SO.sub.2 --Y                                      part of a ring or                                                              chain                                                                      __________________________________________________________________________

The chemistry of Table 1 can be carried out in aprotic solvents such as a chlorocarbon, pyridine, benzene or toluene, at temperatures ranging from -20° C. to the reflux point of the solvent and with or without a trialkylamine base.

                                      TABLE 2                                      __________________________________________________________________________     Preparation of ketone linkages between A and B.                                             then the reactive                                                                         to give the                                              Rxn.  substituent of following product                                         No. if A contains : Y is : A--X--Y :                                         __________________________________________________________________________     1  A--C(O)Cl BrMg--Y    A--C(O)--Y                                               2 A--CR.sup.3 R.sup.3' C(O)Cl BrMg--Y A--CR.sup.3 R.sup.3'.sub.2                                     C(O)--Y                                                  3 A--C(O)Cl BrMgCR.sup.3 R.sup.3' --Y A--C(O)CR.sup.3 R.sup.3' --Y                                    4 A--CR.sup.3 R.sup.3' C(O)Cl BrMgCR.sup.3                                    R.sup.3' --Y A--CR.sup.3 R.sup.3' C(O)CR.sup.3                                 R.sup.3' --Y                                           __________________________________________________________________________

The coupling chemistry of Table 2 can be carried out by a variety of methods. The Grignard reagent required for Y is prepared from a halogen analog of Y in dry ether, dimethoxyethane or tetrahydrofuran at 0° C. to the reflux point of the solvent. This Grignard reagent can be reacted directly under very controlled conditions, that is low temeprature (-20° C. or lower) and with a large excess of acid chloride or with catalytic or stoichiometric copper bromide.dimethyl sulfide complex in dimethyl sulfide as a solvent or with a variant thereof. Other methods available include transforming the Grignard reagent to the cadmium reagent and coupling according to the procedure of Carson and Prout (Org. Syn. Col. Vol. 3 (1955) 601) or a coupling mediated by Fe(acac)₃ according to Fiandanese et al. (Tetrahedron Lett., (1984) 4805), or a coupling mediated by manganese (II) catalysis (Cahiez and Laboue, Tetrahedron Lett., 33(31), (1992) 4437).

                  TABLE 3                                                          ______________________________________                                         Preparation of ether and thioether linkages between A and B                                          then the reactive                                                                         to give the                                     Rxn.  substituent of following                                                 No. if A contains : Y is : product A--X--Y :                                 ______________________________________                                         1     A--OH       Br--Y        A--O--Y                                           2 A--CR.sup.3 R.sup.3' --OH Br--Y A--CR.sup.3 R.sup.3' O--Y                    3 A--OH Br--CR.sup.3 R.sup.3' --Y A--OCR.sup.3 R.sup.3' --Y                    4 A--SH Br--Y A--S--Y                                                          5 A--CR.sup.3 R.sup.3' --SH Br--Y A--CR.sup.3 R.sup.3' S--Y                    6 A--SH Br--CR.sup.3 R.sup.3' --Y A--SCR.sup.3 R.sup.3' --Y                  ______________________________________                                    

The ether and thioether linkages of Table 3 can be prepared by reacting the two components in a polar aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide in the presence of a base such as potassium carbonate, sodium hydride or potassium t-butoxide at temperature ranging from ambient temperature to the reflux point of the solvent used.

                  TABLE 4                                                          ______________________________________                                         Preparation of --SO--and --SO2--linkages from                                    thioethers of Table 3.                                                                                        and it is oxidized                                and it is oxidized with m-chloroper-                                           with Alumina (wet)/ benzoic acid (Satoh                                       if the Oxone (Greenhalgh, et al., Chem. Lett.                                 Rxn. starting Synlett, (1992) 235) (1992) 381, the                             No. material is : the product is : product is :                              ______________________________________                                         1    A--S--Y     A--S(O)--Y    A--SO.sub.2 --Y                                   2 A--CR.sup.3 R.sup.3' S--Y A--CR.sup.3 R.sup.3' S(O)--Y A--CR.sup.3                                        R.sup.3' SO.sub.2 --Y                             3 A--SCR.sup.3 R.sup.3' --Y A--S(O)CR.sup.3 R.sup.3' --Y A--SO.sub.2                                        CR.sup.3 R.sup.3' --Y                           ______________________________________                                    

The thioethers of Table 3 serve as a convenient starting material for the preparation of the sulfoxide and sulfone analogs of Table 4. A combination of wet alumina and oxone provides a reliable reagent for the oxidation of the thioether to the sulfoxide while m-chloroperbenzoic acid oxidation will give the sulfone.

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration fo the invention and are not intended to be limiting thereof.

EXAMPLES

The synthesis of representative compounds according to the invention is described in further detail below with reference to the following specific, but non-limiting examples.

Abbreviations used in the Examples are defined as follows: "°C." for degrees Celsius, "d" for doublet, "dd" for doublet of doublets, "DAST" for diethylaminosulfur trifluoride, "eq" for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "mL" for milliliter or milliliters, "H" for hydrogen or hydrogens, "hr" for hour or hours, "m" for multiplet, "M" for molar, "min" for minute or minutes, "MHz" for megahertz, "MS" for mass spectroscopy, "nmr" or "NMR" for nuclear magnetic resonance spectroscopy, "t" for triplet, "TLC" for thin layer chromatography.

Examples 1-15 were prepared by Michael addition of 5-cyano-benzimidazole to the α,β-unsaturated esters by using K₂ CO₃ (2 mmol) as a base in DMF (10 mL) at 90-110° C. for 16-24 hours, followed by the Pinner reaction. A mixture of meta- and para-isomers was obtained by purification on TLC plates with 10-20% MeOH in CH₂ Cl₂. The pure meta- or para-isomer was separated by HPLC. ##STR33##

A solution of 4-amino-3-nitrobenzonitrile (20 mmol) in MeOH (300 mL) in the presence of 5% of Pd/C (1 g) was treated with hydrogen at room temperature for 16 hours. The reaction mixture was filtered and concentrated to give 3,4-diaminobenzonitrile (2.4 g, 90% of yield), which was directly treated with formic acid (20 mL) under reflux for 4 hours. After removal of the excess formic acid, the residue was dissolved in EtOAc, washed with 10% sodium bicarbonate and brine, and dried over MgSO₄. Concentration gave 5-cyanobenzimidazole (2.2 g, 85%). ¹ H NMR (CD₃ OD) δ8.39 (s, 1H), 8.05 (s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.59 (dd, J=8.4 Hz, J=1.1 Hz, 1H); MS: 144 (M+H)⁺.

Preparation of Ethyl 2-(3-cyanophenyl)ethacrylate and Ethyl 2-(4-cyanophenyl)ethacrylate

To a stirred suspension of zinc powder (22 mmol) in THF (10 mL) was added 1,2-dibromoethylene (0.2 g) at room temperature and the mixture was stirred for 30 minutes. A solution of 3-cyanobenzylbromide or 4-cyanobenzylbromide (20 mmol) in THF (25 mL) was slowly added at a rate of one drop per five seconds at 5-10° C. The mixture was stirred for 3 hours, and then transferred into a solution of copper (I) cyanide (20 mmol) and lithium chloride (40 mmol) in THF (20 mL) at -78° C. The resulting mixture was warmed up and stirred at -20° C. for 20 minutes, and was then cooled to -78° C. After ethyl 2-(bromomethyl)acrylate (20 mmol) was slowly added, the mixture was stirred at -78° C. for 2 hours, and then warmed to room temperature overnight. Ether (100 mL) and aqueous saturated ammonium chloride (50 mL) were added to the mixture and the mixture filtered. The filtrate was washed with water and brine, and dried over MgSO₄. Concentration gave a residue, which was purified by column chromatography with gradient solvent system (CH₂ Cl₂ -EtOAc) to give ethyl 2-(3-cyanophenyl)ethacrylate (1.2 g, 26.2%) and ester ethyl 2-(4-cyanophenyl)ethacrylate (3.6 g, 78.6%).

For ethyl 2-(4-cyanophenyl)ethacrylate: ¹ H NMR (CDCl₃) δ7.58 (dd, J=8.4 Hz, J=1.8 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 6.17 (d, J=1.1 Hz, 1H), 5.48 (dd, J=2.6 Hz, J=1.1 Hz, 1H), 4.22 (q, J=7.3 Hz, 2H), 2.86 (dd, J=8.6 Hz, J=7.1 Hz, 2H), 2.61 (dd, J=8.6 Hz, J=7.0 Hz, 2H), 1.32 (t, J=7.0 Hz, 3H); MS: 247 (M+NH₄)⁺.

For ethyl 2-(3-cyanophenyl)ethacrylate: ¹ H NMR (CDCl₃) δ7.51-7.36 (m, 4H), 6.17 (s, 1H), 5.48 (d, J=1.1 Hz, 1H), 4.22 (q, J=7.3 Hz, 2H), 2.84 (dd, J=8.4 Hz, J=7.0 Hz, 2H), 2.61 (dd, J=8.4 Hz, J=7.0 Hz, 2H), 1.32 (t, J=7.0 Hz, 3H); ¹³ C NMR (CDCl₃) δ166.80, 142.85, 139.41, 133.14, 132.05, 129.85, 129.17, 118.94, 112.43, 60.79, 34.50, 33.57, 14.22; MS 247 (M+NH₄)⁺.

Preparation of Ethyl [3-(4-cyanophenyl)-2-bromomethyl]acrylate

To a solution of 4-cyanobenzylbromide (40 mmol) in xylene (40 mL) was added triphenylphosphine (40 mmol) and the resulting solution was heated at 110° C. for 2 hours. After removal of xylene, a white solid was obtained, which was dissolved in a mixture of THF (40 mL) and EtOH (40 mL), treated with DBU (40 mmol) at room temperature for one hour, and then to it was added ethyl pyruvate (40 mmol). The resulting mixture was stirred at room temperature overnight and filtrated to remove Ph₃ PO. The filtrate was concentrated, dissolved in EtOAc, washed with 1 N HCl, water and brine, and dried over MgSO₄. Concentration gave a mixture of cis and trans olefins in almost quantitative yield. A solution of the olefins (5 mmol), NBS (5 mmol), and AIBN (0.25 mmol) in CCl₄ (200 mL) was refluxed under nitrogen for 16 hours, filtered, concentrated and purified by column chromatography with gradient solvent system (CH₂ Cl₂ -EtOAc) to give the title compound (1.25 g, 85%) as a white solid. ¹ H NMR (CDCl₃) δ7.71 (d, J=1.4 Hz, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.58 (J=8.5 Hz, 2H), 4.29 (q, J=7.3 Hz, 2H), 4.23 (s, 2H), 1.32 (t, J=7.3 Hz, 3H).

Preparation of Ethyl 2-(4-benzyloxyphenyl)methacrylate

A mixture of 4-bromophenol (40 mmol), benzylbromide (40 mmol) and Na₂ CO₃ in DMF (200 mL) was stirred at room temperature for 24 hours and was then poured into water. A solid was collected and was further recrystallized from hexane to give 4-benzyloxybenzene bromide in almost quantitative yield. A solution of the bromide in THF (100 mL) was treated with BuLi (44 mmol) at -78° C. over 30 minutes and then with a solution of ZnI₂ (40 mmol) in THF (40 mL) over 20 minutes. After the resulting mixture was warmed to room temperature over an hour, it was cooled to -78° C. and a solution of copper (I) cyanide (40 mmol) and lithium chloride (80 mmol) in THF (50 mL) was slowly added. The resulting mixture was warmed and stirred at -20° C. for 20 minutes, cooled to -78° C., and to it was added ethyl 2-(bromomethyl)acrylate (40 mmol). The resulting mixture was stirred at -78° C. for 2 hours and was then warmed to room temperature overnight. Ether and aqueous saturated ammonium chloride were added and filtered. The filtrate was washed with water and brine, and dried over MgSO₄. Concentration gave a residue, which was purified by column chromatography with gradient solvent system (CH₂ Cl₂ -EtOAc) to give the title compound (3.6 g, 30.4%): ¹ H NMP (CDCl₃) δ7.44-7.26 (m, 5H),7.12 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 6.20 (s, 1H), 5.92 (s, 1H), 5.07 (s, 2H), 4.18 (q, J=7.4 Hz, 2H), 3.57 (s, 2H), 1.27 (t, J=7.4 Hz, 3H); MS: 314 (M+NH₄)⁺.

EXAMPLE 1

Preparation of Ethyl 2-(3-amidinophenyl)ethyl-3-(5-amidinobenzimidazole)propionate and Ethyl 2-(3-amidinophenyl)ethyl-3-(6-amidinobenzimidazole)propionate

A mixture of 5-cyanobenzimidazole (2 mmol), ethyl 2-(3-cyanophenyl)ethacrylate (2 mmol) and K₂ CO₃ (2 mmol) in DMF (10 mL) was heated at 90° C. under nitrogen for 16 hours. The mixture was diluted with EtOAc (150 mL), washed with 1 N HCl, water, and brine, and dried over MgSO₄. After filtration and concentration, a residue was purified by column chromatography with gradient solvent system (CH₂ Cl₂ -EtOAc) to give a mixture of ethyl 2-(3-cyanophenyl)ethyl-3-(6-cyanobenzimidazole)propionate and ethyl 2-(3-cyanophenyl)methyl-3-(5-cyanobenzimidazole)propionate (0.57 g, 76.4%) as a colorless oil. ¹ H NMR (CDCl₃) δ8.13-7.36 (m, 8H), 4.55 (dd, J=14.3 Hz, J=9.2 Hz, 1H), 4.28 (dd, J=14.3 Hz, J=5.5 Hz, 1H), 4.07 (q, J=7.0 Hz, 2H), 3.00-2.91 (m, 1H), 2.80-2.64 (m, 2H), 2.18-2.07 (m, 1H), 1.92-1.82 (m, 1H), 1.12 (t, J=7.0, 3H).

EXAMPLES 2 AND 3

Preparation of Ethyl 2-(3-amidinophenyl)ethyl-3-(5-amidinobenzimidazole)propionate and Ethyl 2-(3-amidinophenyl)ethyl-3-(6-amidinobenzimidazole)propionate

The mixture of esters obtained in Example 1 was treated with HCl (gas) in anhydrous ethanol (10 mL) for 15 minutes at 0° C. and then stirred for 16 hours. After removal of excess HCl (gas) and ethanol, the residue was treated with (NH₄)₂ CO₃ (5 equivalents) in anhydrous ethanol (10 mL) at room temperature for 24 hours. Concentration gave a residue, which was purified on TLC plates with 10% MeOH in CH₂ Cl₂ to give a mixture of the title compounds (400 mg, 65.4%): mp 160-165° C.; ESMS: 204.2 (M+2H)²⁺. The mixture was further separated by HPLC on chiral OJ column with CO₂ /MeOH/TEA (80/20/0.1) to give Example 2, ethyl 2-(3-amidinophenyl)ethyl-3-(5-amidinobenzimidazole)propionate, and Example 3, ethyl 2-(3-amidinophenyl)ethyl-3-(6-amidinobenzimidazole)propionate.

Example 2: ¹ H NMR (CD₃ OD) δ8.36 (s, 1H), 8.17 (s, 1H), 7.75-7.72 (m, 2H), 7.63 (bs, 2H), 7.50-7.48 (m, 2H), .4.66 (dd, J=9.5 Hz, J=14.3 Hz, 1H), 4.55 (dd, J=5.5 Hz, J=14.2 Hz, 1H), 4.02-3.92 (m, 2H), 3.14-3.08 (m, 1H), 2.81 (t, J=7.0 Hz, 2H), 2.19-1.93 (m, 2H), 1.04 (t, J=7.0 Hz, 3H); ESMS: 204.2 (M+2H)²⁺.

Example 3: ¹ H NMR (CD₃ OD) δ8.37 (s, 1H), 8.10 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.65-7.62 (m, 2H), 7.55-7.46 (m, 2H), 4.68 (dd, J=9.5 Hz, J=14.3 Hz, 1H), 4.56 (dd, J=5.5 Hz, J=14.2 Hz, 1H), 4.04-3.94 (m, 2H), 3.24-3.18 (m, 1H), 2.83 (t, J=7.0 Hz, 2H), 2.19-1.95 (m, 2H), 1.05 (t, J=7.0 Hz, 3H); ESMS: 204.2 (M+2H)²⁺.

EXAMPLE 4

Preparation of Ethyl 2-(4-amidinophenyl)ethyl-3-(5-amidinobenzimidazole)propionate and Ethyl 2-(4-amidinophenyl)ethyl-3-(6-amidinobenzimidazole)propionate

Example 4 was made using the same method as described for Example 1, except ethyl 2-(4-cyanophenyl)ethacrylate (2 mmol) was used (100 mg, 13% for two steps): mp 230° C. (Dec.); ESMS: 407 (M+H)⁺ ; HRMS: 407.2200 (obs.), 407.2195 (calcd.) for C₂₂ H₂₆ N₆ O₂. Example 4 was further separated to give Examples 5 and 6.

EXAMPLES 5 AND 6

Preparation of Ethyl 2-(4-amidinophenyl)ethyl-3-(5-amidinobenzimidazole)propionate and Ethyl 2-(4-amidinophenyl)ethyl-3-(6-amidinobenzimidazole)propionate

The mixture of compounds obtained in Example 4 were further separated to give Examples 5 and 6.

Example 5, ethyl 2-(4-amidinophenyl)ethyl-3-(5-amidinobenzimidazole)propionate: ¹ H NMR (DMSO-d₆): δ9.43-9.08 (m, 6H), 7.74-7.65 (m, 2H), 7.40-7.38 (m, 2H), 7.35-7.00 (m, 4H), 4.67-4.55 (m, 2H), 4.06 (bs, 2H), 3.48 (bs, 2H), 3.20 (bs, 1H), 2.70 (bs, 2H), 1.00 (bs, 3H); ESMS: 407 (M+H)⁺.

Example 6, ethyl 2-(4-amidinophenyl)ethyl-3-(6-amidinobenzimidazole)propionate: ¹ H NMR (DMSO-d₆): δ9.23-9.12 (m, 6H), 8.41 (s, 1H), 8.21 (s, 1H), 7.84-7.82 (m, 1H), 7.74 (d, J=8.1 Hz, 2H), 7.41 (d, J=7.8 Hz, 2H), 7.24 (bs, 1H), 4.58-4.56 (m, 2H), 3.95-3.89 (m, 2H), 3.10-3.00 (m, 1H), 2.73-2.71 (m, 2H), 1.90-1.88 (m, 2H), 0.98-0.96 (m, 3H); ESMS: 407 (M+H)⁺.

EXAMPLE 7

Preparation of Ethyl [3-(4-amidinophenyl)-2-(5-amidinobenzimidazole)methyl]acrylate

A mixture of 5-cyanobenzimidazole (2 mmol), ethyl [3-(4-cyanophenyl)-2-bromomethyl]acrylate (2 mmol) and K₂ CO₃ (2 mmol) in DMF (10 mL) was heated at 90° C. under nitrogen for 24 hours. The mixture was diluted with EtOAc (150 mL), washed with 1 N HCl, water, and brine, and dried over MgSO₄. After filtration and concentration, the residue was purified by column chromatography (CH₂ Cl₂ -EtOAc) to give ethyl [3-(4-cyanophenyl)-2-(5-cyanobenzimidazole)methyl]acrylate (0.401 g, 56.3%) as a colorless oil. ¹ H NMR (CDCl₃) δ8.10-8.00 (m, 4H), 7.83-7.77 (m,, 2H), 7.52-7.44 (m, 2H), 7.01-6.98 (m, 1H), 5.20 (s, 2H), 4.24 (q, J=7.3 Hz, 2H), 1.25 (t, J=7.3 Hz, 3H); MS: 357 (M+H)⁺.

The Pinner reaction converted ethyl [3-(4-cyanophenyl)-2-(5-cyanobenzimidazole)methyl]acrylate (0.42 mmol) to the title compound (400 mg, 65.4%): ¹ H NMR (CD₃ OD) δ8.19-8.12 (m, 2H), 7.92-7.88 (m, 3H), 7.74-7.69 (m, 4H), 4.22-4.19 (m, 2H), 1.24-1.20 (m, 3H); ESMS: 196.2 (M+2H)²⁺ ; HRMS: 391.1889 (obs.), 391.1882 (cal'd.).

EXAMPLE 8

Preparation of Ethyl 2-(4-amidinophenyl)methyl-3-(6-amidinobenzimidazole)propionate and Ethyl 2-(4-amidinophenyl)methyl-3-(5-amidinobenzimidazole)propionate

Ethyl [3-(4-cyanophenyl)-2-(5-cyanobenzimidazole)methyl]acrylate was hydrogenated in MeOH in the presence of 10% palladium on active carbon to give ethyl 2-(4-cyanophenyl)methyl-3-(6-cyanobenzimidazole)propionate and ethyl 2-(4-cyanophenyl)methyl-3-(5-cyanobenzimidazole)propionate: ¹ H NMR (CDCl₃) δ8.24-8.02 (m, 2H), 7.87-7.50 (m,, 4H), 7.34-7.28 (m, 2H), 4.58-4.55 (m, 1H), 4.32-4.27 (m, 1H), 4.12-3.93 (m, 2H), 3.20-2.91 (m, 2H), 2.79-2.72 (m, 1H), 1.10-0.95 (m, 3H).

The mixture obtained (1.5 mmol) was subjected to the Pinner reaction to obtain the title compound (300 mg, 48%): ¹ H NMR (CD₃ OD): δ8.63 (bs, 1H), 8.27-7.96 (m, 7H), 4.98-4.54 (m, 2H), 3.98-3.80 (m, 2H), 3.53-3.45 (m, 1H), 3.37-3.09 (m, 2H), 1.00-0.96 (m, 3H); ESMS: 197 (M+2H)²⁺.

Examples 51-63 were prepared by Method A, B, or C. All compounds were finally purified by HPLC (CH₃ CN/H₂ /0.05% TFA).

Method A: Examples 51-59 were made by Suzuki coupling reactions of [(4-bromophenyl)carbonyl]methyl-6-cyanobenzimidazole or [(4-bromophenyl)carbonyl]methyl-5-cyanobenzimidazole with a variety of boronic acids by using Na₂ CO₃ (2-4 equivalents) and Pd(PPh₃)₄ (5-10% mmol⁻¹) as catalyst in THF (80% in H₂ O, 10 mL/mmol), followed by Pinner reactions.

A mixture of [(4-bromophenyl)carbonyl]methyl-6-cyanobenzimidazole and [(4-bromophenyl)carbonyl]methyl-5-cyanobenzimidazole was made in over 90% yield by alkylation of 5-cyano-benzimidazole (36 mmol) with 2,4'-dibromoacetophenone (36 mmol) by using NaH (48 mmol) as a base in THF (80 mL). The mixture were isolated by HPLC on chiralcel OJ column with MeOH/CO₂ (20/80) to give pure individual compounds.

[(4-Bromophenyl)carbonyl]methyl-6-cyanobenzimidazole: ¹ H NMR (CDCl₃) δ8.35 (s, 1H), 8.11 (dd, J=1.1 Hz, J=0.7 Hz, 1H), 8.08 (d, J=8.8 Hz, 2H), 7.81 (d, J=8.4 Hz, 2H), 7.56 (dd, J=8.4 Hz, J=1.8 Hz, 1H), 6.16 (s, 1H); ESMS: 340/342 (M+H)⁺.

[(4-Bromophenyl)carbonyl]methyl-5-cyanobenzimidazole: ¹ H NMR (CDCl₃) δ8.31 (s, 1H), 8.13 (t, J=0.7 Hz, 1H), 8.07 (d, J=8.8 Hz, 2H), 7.81 (d, J=8.8 Hz, 2H), 7.75 (dd, J=8.4 Hz, J=0.7 Hz, 1H), 7.57 (dd, J=8.4 Hz, J=1.1 Hz, 1H), 6.15 (s, 1H); ESMS: 340/342 (M+H)⁺.

EXAMPLE 51

Preparation of [4-(phenyl)phenylcarbonyl]methyl-6-amidinobenzimidazole

MP: 155-157° C.; ¹ H NMR (CD₃ OD) δ8.44 (s, 1H) 8.23 (d, J=8.4 Hz, 1H), 8.07 (d, J=1.1 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.88 (dd, J=8.4, 2H), 7.72 (dd, J=8.4 Hz, J=1.1 Hz, 3H), 7.52-7.41 (m, 3H), 6.10 (s, 2H); MS: 355 (M+H)⁺, HRMS: 355.1554 (obs.), 355.1:559 (calcd.); Anal.: (C₂₂ H₁₈ N₄ O₁ +0.9TFA+1.2HCl+0.5H₂ O) C, H, N, F, Cl.

EXAMPLE 52

Preparation of [4-(phenyl)phenylcarbonyl]methyl-5-amidinobenzimidazole

MP: 260-261° C.; ¹ H NMR (CD₃ OD) δ8.41 (s, 1H), 8.22 (s, 1H), 8.20 (d, J=8.8 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H), 7.73-7.70 (m, 4H), 7.51-7.41 (m, 3H), 6.10 (s, 2H); MS: 355.2 (M+H)⁺ ; HRMS: 355.1538 (obs.), 355.1559 (calcd.); Anal.: (C₂₂ H₁₈ N₄ O₁ +1.5TFA+0.08HCl+1H₂ O) C, H, N, Cl.

EXAMPLE 53

Preparation of [4-(3-aminophenyl)phenylcarbonyl]methyl-6-amidinobenzimidazole

¹ H NMR (DMSO-d₆) δ9.22 (s, 1.5 H), 9.04 (s, 1.5 H), 8.48 (s, 1H), 8.22 (d, J=1.4 Hz, 1H), 8.18 (d, J=8.3 Hz, 2H), 7.91 (d, J=8.5 Hz, 1H), 7.84 (d, J=8.5 Hz, 2H), 7.69 (dd, J=8.6 Hz, 1.7 Hz, 1H), 7.21 (t, J=1.8 Hz, 1H), 7.04 (s, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.73 (d, J=8.1 Hz, 1H), 6.14 (s, 2H); ¹³ C NMR (DMSO-d₆) δ192.4, 165.9, 148.6, 147.6, 146.7, 146.2, 139.3, 134.3, 132.9, 129.7, 128.8, 126.8, 121.8, 121.3, 119.7, 115.6, 115.1, 113.0, 111.8, 51.0; MS: 370 (M+H)⁺ ; HRMS: 370.1664 (obs.), 370.1668 (calcd.)

EXAMPLE 54

Preparation of [4-(3-aminophenyl)phenylcarbonyl]methyl-5-amidinobenzimidazole

¹ H NMR (CD₃ OD) δ8.48 (s, 1H), 8.32 (d, J=8.4 Hz, 2H), 7.87 (d, J=845 Hz, 2H), 7.74 (s, 2H), 7.62-7.56 (m, 2H), 7.53 (d , J=8.4 Hz, 2H), 7.25 (d, J=7.4 Hz, 1H), 6.12 (s, 2H); MS: 370 (M+H)⁺, HRMS: 370.1664 (obs.), 370.1668 (calcd.)

EXAMPLE 55

Preparation of [4-(4-fluorophenyl)phenylcarbonyl]methyl-6-amidinobenzimidazole

MP: 102-105° C.; ¹ H NMR (CD₃ OD) δ8.54 (bs, 1H), 8.23 (d, J=8.8 Hz, 2H), 8.10 (bs, 1H), 7.92 (bs, 1H), 7.86 (d, J=8.4 Hz, 2H); ¹⁹ F NMRδ-116.3, -77.65 (TFA); ¹³ C NMR (CD₃ OD) δ192.9, 168.6, 165.0, 163.5, 147.2, 137.1, 134.3, 130.3, 130.2, 130.1, 128.5, 124.7, 123.4, 120.8, 117.1, 116.9, 112.9, 52.5; MS: 373.2 [(M+H)⁺ ; HRMS: 373.1481 (obs.), 373.1465 (calcd.); Anal.: (C₂₂ H₁₇ N₄ O₁ F₁ +1.9TFA+0.1HCl+2H₂ O) C, H, N, F, Cl.

EXAMPLE 56

Preparation of [4-(4-formylphenyl)phenylcarbonyl]methyl-6-amidinobenzimidazole

MP: 125-128° C.; ¹ H NMR (CD₃ OD) δ10.05 (s, 1H), 8.48 (s, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.07 (bs, 1H), 8.05 (d, J=8.4 Hz, 2H), 7.97 (d, J=8.1 Hz, 2H), 7.95 (d, J=8.1 Hz, 2H), 7.93 (d, J=8.4 Hz, 2H), 7.73 (dd, J=8.4 Hz, J=1.8 Hz, 1H), 6.12 (s, 2H); ¹³ C NMR (CD₃ OD) δ192.99, 168.67, 147.86, 140.90, 140.15, 134.44, 130.10, 128.64, 128.57, 128.09, 124.63, 123.41, 120.75, 112.87, 104.26, 54.45; MS: 192.2 (M+2H)²⁺ ; HRMS: 383.1531 (obs.), 383.1508 (calcd.).

EXAMPLE 57

Preparation of [4-(2-aminosulfonylphenyl)phenylcarbonyl]methyl-6-amidinobenzimidazole

MP: 126-128° C.; ¹ H NMR (CD₃ OD) δ8.55 (bs, 1H), 8.18 (d, J=8.4 Hz, 2H), 8.13 (dd, J=7.7 Hz, J=1.4 Hz, 1H), 8.09 (s, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.71 (dd, J=8.4 Hz, J=1.4 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.65 (d, J=8.1 Hz, 2H), 7.60 (dd, J=7.8 Hz, J=1.4 Hz, 1H), 7.36 (dd, J=7.3 Hz, J=1.4 Hz, 1H), 6.13 (s, 2H); MS: 217.7 (M+2H)²⁺ ; HRMS: 434.1303 (obs.), 434.1287 (calcd.)

EXAMPLE 58

Preparation of [4-(2-tert-butylaminosulfonylphenyl)phenylcarbonyl]methyl-6-amidinobenzimidazole

MP: 118-120° C.; ¹ H NMR (CD₃ OD) δ8.60 (bs, 1H), 8.19 (d, J=8.4 Hz, 2H), 8.13 (dd, J=7.7 Hz, J=1.4 Hz, 1H), 8.09 (s, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.76 (dd, J=8.4 Hz, J=1.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.63 (dd, J=7.7 Hz, J=1.5 Hz, 1H), 7.60 (dd, J=7.7 Hz, J=1.4 Hz, 1H), 7.34 (dd, J=7.7 Hz, J=1.4 Hz, 1H), 6.14 (s, 2H), 1.09 (s, 9H); ¹³ C NMR (CD₃ OD) δ193.25, 168.78, 149.52, 147.86, 143.50, 140.87, 134.76, 133.27, 133.07, 132.83, 131.58, 130.45, 129.77, 129.49, 128.76, 127.34, 124.45, 123.22, 120.99, 112.68, 55.30, 52.38, 30.22; Anal.: (C₂₆ H₂₇ N₅ O₃ S₁ +1.9TFA+1H₂ O) C, H, N, F, S, Cl.

EXAMPLE 59

Preparation of {4-[(2-tetrazolyl)phenyl]phenylcarbonyl}methyl-6-amidinobenzimidazole

MP: 144-145° C.; ¹ H NMR (CD₃ OD) δ8.56 (bs, 1H), 8.11-8.09 (m, 3H), 7.93 (d, J=8.5 Hz, 1H), 7.76 (dd, J=8.5 Hz, J=1.7 Hz, 1H), 7.73 (d, J=7.3 Hz, 2H), 7.67-7.62 (m, 2H), 7.38 (d, J=8.8 Hz, 2H), 6.09 (s, 2H); ¹³ C NMR (CD₃ OD) δ192.97, 168.66, 156.91, 149.40, 147.07, 146.51, 142.32, 135.60, 134.66, 132.64, 131.79, 131.71, 130.90, 129.88, 129.47, 124.56, 123.43, 120.75, 112.87, 52.45; MS: 212.2 (M+2H)²⁺ ; HRMS: 423.1686 (obs.), 423.1682(calcd.); Anal.: (C₂₃ H₁₈ N₈ O₁ +1.9TFA+1 HCl+0.5H₂ O) C, H, N, F, S, Cl.

Method B: Examples 60, 61 and 62 were made by alkylation of 5-cyanobenzimidazole with [4-(2-tert-butylaminosulfonylphenyl)phenylaminocarbonyl]methylene chloride, or (4-benzylpiperidinecarbonyl)methylene chloride, followed by Pinner reactions.

EXAMPLES 60 AND 61

Preparation of [4-(2-aminosulfonylphenyl)phenylaminocarbonyl]methyl-6-amidinobenzimidazole (Example 60) and [4-(2-aminosulfonylphenyl)phenylaminocarbonyl]methyl-5-amidinobenzimidazole (Example 61)

[4-(2-tert-Butylaminosulfonylphenyl)phenylaminocarbonyl]methylene chloride was prepared by acylation of 4-[(o-SO₂ NHtBu)phenyl]aniline (3 mmol) with α-chloroacetyl chloride (4 mmol) in CH₃ CN (100 mL) and K₂ CO₃ (4 mmol).

Alkylation of 5-cyanobenzimidazole (2 mmol) with [4-(2-tert-butylaminosulfonylphenyl)phenyl-aminocarbonyl]methylene chloride (2 mmol) in DMF (10 mL) and K₂ CO₃ (4 mmol) at r.t. over 16 hours, followed by purification on thin layer TLC plates, and further isolation by HPLC gave [4-(2-tert-butylaminosulfonylphenyl)phenylaminocarbonyl]methyl-6-cyanobenzimidazole (240 mg, 56%) and [4-(2-tert-butylaminosulfonylphenyl)phenylaminocarbonyl]methyl-5-cyanobenzimidazole (160 mg, 37%).

[4-(2-tert-Butylaminosulfonylphenyl)phenylaminocarbonyl]methyl-6-cyanobenzimidazole was converted to Example 60 via the Pinner reaction and purified by HPLC: MP: 134-136° C.; ¹ H NMR (CD₃ OD) δ8.73 (bs, 1H), 8.15 (s, 1H), 8.10 (dd, J=8.6 Hz, J=1.2 Hz, 1H), 7.93 (d, J=8.3 Hz, 1H), 7.75 (d, J=7.4 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.60 (dd, J=7.6 Hz, J=1.2 Hz, 1H), 7.52 (td, J=7.6, J=1.4 Hz, 1H), 7.40 (d, J=8.8 Hz, 2H), 7.32 (dd, J=7.6 Hz, J=1.2 Hz, 1H), 5.36 (s, 2H); ¹³ C NMR (CD₃ OD) δ168.79, 166.75, 143.05, 141.48, 138.93, 137.50, 133.63, 132.92, 131.28, 128.75, 128.59, 124.63, 123.35, 120.96, 120.53, 112.80, 47.51; MS: 449.3 (M+H)⁺ ; HRMS: 449.1401 (obs.), 449.1396 (Calcd.); Anal.: (C₂₂ H₂₀ N₆ O₃ S₁ +1.8TFA+0.25 HCl+1H₂ O) C, H, N, F, S, Cl.

[4-(2-tert-Butylaminosulfonylphenyl)phenylaminocarbonyl]methyl-5-cyanobenzimidazole was converted to Example 61 via the Pinner reaction and purified by HPLC: MP: 254° C. (Dec.); ¹ H NMR (CD₃ OD) δ8.55 (s, 1H), 8.22 (s, 1H), 8.08 (d, J=6.6 Hz, 1H), 7.83-7.75 (m, 2H), 7.62 (d, J=8.8, 2H), 7.59-7.52 (m, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.31 (d, J=7.4 Hz, 1H), 5.33 (s, 2H); ¹³ C NMR (DMSO-d₆) δ165.73, 164.97, 147.72, 142.58, 142.19, 139.43, 138.17, 137.63, 135.23, 132.31, 131.35, 129.69, 127.39, 127.23, 122.20, 121.03, 120.96, 120.17, 118.21, 118.12, 111.24, 47.51; MS: 449.3 (M+H)⁺ ; HRMS: 449.1414 (obs.), 449.1396 (calcd.); Anal.: (C₂₂ H₂₀ N₆ O₃ S₁ +2TFA+0.15 HCl+1.5H₂ O) C, H, N, F, S, Cl.

EXAMPLE 62

Preparation of 1-(4-benzylpiperidinecarbonyl)methyl-6-amidinobenzimidazole and 1-(4-benzylperidinecarbonyl)methyl-5-amidinobenzimidazole

(4-Benzylpiperidinecarbonyl)methylene chloride was prepared by acylation of 4-benzylpiperidine (100 mmol) with a-chloroacetyl chloride (100 mmol) in THF (250 mL) and K₂ CO₃ (100 mL. Alkylation of 5-cyanobenzimidazole (2 mmol) with (4-benzylpiperidinecarbonyl)methylene chloride (2 mmol) in DMF (5 mL) in the presence of NaH (3 mmol) at from 0° C. to room temperature over 16 hours, followed by purification on TLC plates gave 1-(4-benzylpiperidinecarbonyl)methyl-6-cyanobenzimidazole and 1-(4-benzylpiperidinecarbonyl)methyl-5-cyanobenzimidazole (0.4 g, 56% of yield). This mixture (1.11 mmol) was then carried through the Pinner reaction, followed by purification on TLC plates with 10% MeOH in CH₂ Cl₂, and further purification by HPLC to give the title compounds: MP: 54-56° C.; MS: 376.4 (M+H)⁺ ; HRMS:376.2118 (obs.), 376.2137 (calcd.); Anal.: (C₂₂ H₂₅ N₅ O₁ +1.8TFA+0.1 HCl).

Method C: Example 63 was made by Ulmann coupling reaction of 4-chloro-3-nitrobenzenitrile with (4-benzylpiperidinecarbonyl)methylamine, followed by reduction of 4-[(4-benzylpiperidinecarbonyl)methyl]amino-3-nitrobenzonitrile, cyclization with formic acid, and finally the Pinner reaction.

EXAMPLE 63

Preparation of 1-(4-benzylpiperidinecarbonyl)methyl-6-amidinobenzimidazole

(4-Benzylpiperidinecarbonyl)methylamine was made by treatment of (4-benzylpiperidinecarbonyl)methylene chloride with NaN₃ in aqueous acetone, followed by hydrogenation with 5% Pd/C. Reaction of (4-benzylpiperidinecarbonyl)methylamine (8.6 mmol) with 4-chloro-3-nitro-benzonitrile (10 mmol) in DMF (10 mL) in the presence of NaHCO₃ (10 mmol) at 100° C. for 16 hours gave 4-[(4-benzylpiperidinecarbonyl)methyl]amino-3-nitrobenzonitrile (1.6 g, 49.2% of yield), which was then hydrogenated in MeOH in the presence of 5% of Pd/C (10% w/w) to produce 1-(4-benzylpiperidinecarbonyl)methyl-6-cyanobenzimidazole (1.3 g, 90% of yield). 1-(4-Benzylpiperidinecarbonyl)methyl-6-cyanobenzimidazole (0.57 mmol) was then carried through the Pinner reaction, followed by purification on TLC plates with 10% MeOH in CH₂ Cl₂, and further purification by HPLC to give the title compound: mp: 68-70° C.; ¹ H NMR (CD₃ OD) δ8.52 (s, 1H), 8.20 (s, 1H), 7.75 (s, 2H), 7.29-7.24 (m, 2H), 7.18-7.16 (m, 3H), 5.43 (dd, J=17.2 Hz, J=24.5 Hz, 2H), 4.40 (d, J=12.8 Hz, 1H), 4.00 (d, J=12.8 Hz, 1H), 3.18 (t, J=12.8 Hz, 1H), 2.68 (t, J=12.8 Hz, 1H), 2.59 (d, J=7.00 Hz, 2H), 1.87-1.78 (m, 2H), 1.72-1.68 (m, 1H, 1.42-1.35 (m, 1H), 1.22-1.15 (m, 1H); ¹³ C NMR (CD₃ OD) δ168.76, 166.06, 148.73, 141.23, 139.50, 130.17, 129.45, 129.33, 127.35, 127.11, 124.04, 120.40, 113.19, 47.38, 46.36, 43.93, 43.73, 39.15, 33.35, 32.73; MS: 188.8 (M+2H)²⁺ ; HRMS:376.2130 (obs.), 376.2137 (calcd.); Anal.: (C₂₂ H₂₅ N₅ O₁ +1.85TFA+0.18HCl+0.5H₂ O).

EXAMPLE 64

Preparation of 2-[4-(2-aminosulfonylphenyl)phenylcarbonyl]methyl-6-amidinobenzimidazole

N-ethylmalonyl-4'-aminobiphenyl-2-tert-butylsulfonamide. To a solution of 1.01 g of 4'-aminobiphenyl-2-tert-butylsulfonamide in 30 mL anhydrous methylene chloride and 0.93 mL triethylamine was added 0.43 mL of ethylmalonyl chloride by dropwise addition. Let reaction mixture stir overnight at ambient temperature. Concentrated in vacuo to give a residue which was taked up in 50 mL ethyl acetate. The organics were washed 3×20 mL water. The resulting organics were dried over magnesium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified via standard chromatographic technique to give 0.70 g of N-ethylmalonyl-4'-aminobiphenyl-2-tert-butylsulfonamide. LRMS(NH₃ -CI): 436(M+NH₄). ¹ H NMR(CDCl₃, 300 MHz): δ9.42 (s, 1H), 8.18 (d, 1H), 7.79 (d, 2H), 7.52 (m, 3H), 7.49 (d, 1H), 7.30 (d, 1H), 4.30 (q, 2H), 3.60 (s, 1H), 3.50 (s, 2H), 1.35 (t, 3H), 1.0 (s, 9H).

2-[4-(2-aminosulfonylphenyl)phenylcarbonyl]methyl-6-cyanobenzimidazole. A mixture of 0.32 g of 3,4-diaminobenzonitrile and 0.70 g of N-ethylmalonyl-4'-aminobiphenyl-2-tert-butylsulfonamide was heated to 180° C. For 20 h. Let mixture cool to ambient temperature. Concentration and high vacuum gave 0.09 g of crude 2-[4-(2-aminosulfonylphenyl)phenylcarbonyl]methyl-6-cyanobenzimidazole. The crude material was carried through to the next reaction sequence. LRMS(ES+): 431(M+H).

2-[4-(2-aminosulfonylphenyl)phenylcarbonyl]methyl-6-amidinobenzimidazole. A solution of the crude 2-[4-(2-aminosulfonylphenyl) phenylcarbonyl]methyl-6-cyanobenzimidazole in 10 mL 1:1 anhydrous chloroform to anhydrous ethanol was stirred in an ice bath. Hydrogen choride gas was bubbled into the reaction vessel for 20 minutes. Then the reaction mixture was allowed to warm to ambient temperature over 15 h. Concentrated the reaction mixture under reduced pressure and placed the crude product on high vacuum. The resultant ethylimidate was treated directly with 0.30 g of ammonium carbonate in anhydrous ethanol. The reaction mixture was stirred at ambient temperature for 24 h. Concentrated reaction mixture under reduced pressure and purified crude product via standard HPLC technique to give purified 2-[4-(2-aminosulfonylphenyl)phenylcarbonyl]methyl-6-amidinobenzimid-azole. LRMS(ES+): 449(m+H). HRMS(FAB): calcd 449.139586 mass 449.139273. ¹ H NMR (DMSO, d6, 300 MHz): δ10.50 (s, 1H), 9.20 (bs, 2H), 8.67 (bs, 2H), 7.79 (d, 2H), 7.55 (m, 4H), 7.25 (m, 4H), 4.05 (s, 2H).

EXAMPLE 65

Preparation of 2-[4-(2-tert-butylaminosulfonylphenyl)phenylcarbonyl]methyl-5-azabenzimidazole

N-ethylmalonyl-4'-aminobiphenyl-2-tert-butylsulfonamide. To a solution of 1.01 g of 4'-aminobiphenyl-2-tert-butylsulfonamide in 30 mL anhydrous THF and 0.93 mL of triethylamine was added 0.43 mL of ethylmalonyl chloride by dropwise addition. Let reaction mixture stir for 24 h. Concentrated in vacuo to give a residue which was taked up in 5 mL ethyl acetate. The organics were washed 3×20 mL water. The resultant organics were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified via standard chromatographic technique to give 0.63 g of N-ethylmalonyl-4'-aminobiphenyl-2-tert-butylsulfonamide. LRMS(NH₃ -CI): 436(M+NH₄). ¹ H NMR(CDCl₃, 300 MHz): δ9.42 (s,1H), 8.18 (d,1H), 7.79 (d,2H), 7.52 (m,3H), 7.49 (d,1H), 7.30 (d,1H).

2-[4-(2-tert-butylaminosulfonylphenyl)phenylcarbonyl]methyl-5-azabenzimidazole. A mixture of 0.026 g of 3,4-diaminopyridine and 0.10 g of N-ethylmalonyl-4'-aminobiphenyl-2-tert-butylsulfonamide was heated to 165° C. for 20 h. Let mixture cool to ambient temperature. Purified crude material by standard chromatographic technique to give the 2-[4-(2-tert-butylaminosulfonylphenyl)phenylcarbonyl]methyl-6-azabenzimidazole. LRMS(ES+): 464(M+H). HRMS(NH₄ -CI): Mass 464.175637 Calcd 464.175630. ¹ H NMR(CDCl₃, 300 MHz): δ9.49 (s,1H), 8.40 (s,1H), 8.15 (d,1H), 7.98 (s,1H), 7.47 (m,3H), 7.31 (d,2H), 7.25 (d,2H), 4.30 (s,2H), 1.0 (s,9H).

EXAMPLE 66

Preparation of 2S-[4-(2-tert-aminosulfonylphenyl)phenylaminocarbonyl]methyl-thio-1H-imidazo(4,5-C) pyridine

To a solution of 1H-imidazo(4,5-C) pyridine-2-thiol (37 mg, 0.245 mmol) in DMF (2.5 mL) was added 4-(2-tert-butylaminosulfonylphenyl)phenylaminocarbonyl]methyl chloride (75 mg, 0.197 mmol) and then K₂ CO₃ (58 mg, 0.42 mmol), and the resulting mixture was heated at 120° C. for 1 hour. To the mixture at room temperature was added HCl (1 N in Et₂ O, 1 mL) and then MeOH (6 mL), a clear solution was obtained. To it was then slowly added Et₂ O (200 ml), and a white suspension was observed, which was filtered and a white solid (120 mg) was collected. The solid was soluble in DMSO (8 mL), and the resulting solution was purified by HPLC with H₂ O--CH₃ CN--TFA to give the title compound (60 mg). HRMS (M+H)⁺ calc. m/z: 496.1477, obs: 496.1492.

EXAMPLE 67

Preparation of 2S-[4-(2-aminosulfonylphenyl)phenylaminocarbonyl]methyl-thio-1H-imidazo(4,5-C) pyridine

A solution of Example 66 (26 mg) in TFA (0.5 mL) was heated for 16 hours. Removed all of the solvent and purified by HPLC with H₂ O--CH₃ CN--TFA to give the title compound (13 mg). HRMS (M+H)⁺ calc. m/z: 440.0851, obs: 440.0831.

EXAMPLE 101

Preparation of 1-(4-benzylpiperidinecarbonyl)methyl-5-amidinoindole

5-Cyanoindole-1-methylacetate. To a stirred solution of 5-cyanoindole (5.0 g, 35.2 mmol) in 10 mL of dry DMF at 0° C. under N₂ atmosphere was added NaH (1.1 g, 42.2 mmol). The reaction was stirred for 30 min. and then α-bromomethylacetate (5.4 g, 35.2 mmol) was added and stirred at room temperature for 2 h. It was then quenched with H₂ O, extracted with ethyl acetate (3×), dried with Na₂ SO₄, filtered and concentrated in vacuo to afford a light yellow solid (7.5 g, 35.2 mmol). ¹ H NMR (CDCl₃) δppm 3.2 (s, 2H), 3.8 (s, 3H), 7.03 (s, 1H), 7.32 (d, 1H, J=7.5Hz), 7.41 (d, 1H, J=7.5Hz), 7.61 (s, 1H), 7.81 (s, 1H). LRMS NH₃ -CI m/z (M+H)⁺ 229, (M+NH₄)⁺ 246.

3-(5-Cyanoindole) acetic acid. Methyl-5-cyanoindole-1-acetate was saponified in MeOH, KOH (3.3 eq) at rt for 18 h. The mixture was concentrated in vacuo, dissolved in water, extracted with diethylether (2×) and the acidic aqueous layer was acidified with 2 N HCl. The resulting white solid was filtered and dried in a vacuum oven to afford 6.2 g of the title compound. LRMS ESI (M+H)⁺ 201.

1-(4-Benzylpiperidinecarbonyl)methyl-5-cyanoindole. To a stirred complex of 3-acetic acid-5-cyanoindole (2.0 g, 0.1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (DEC) in dry CH₂ Cl₂ was added 4-benzylpiperidine (1.8 g, 0.01 mmol). The mixture was stirred under N₂ atmosphere for 18 h, then concentrated in vacuo, dissolved in ethyl acetate, washed with 1 N HCl (3×), NaHCO₃ (3×), brine (2×), dried with Na₂ SO₄, filtered and concentrated in vacuo to afford a white solid (2.8 g). HRMS for C₂₃ H₂₄ N₃ O (M+H)⁺ calc. 358.191938, found 358.193278.

1-(4-Benzylpiperidinecarbonyl)methyl-5-amidinoindole. N-1-Acetyl-1-N'-piperidinyl-4-benzyl-5-cyanoindole (500 mg), was dissolved in dry MeOH (30 mL) cooled to 0° C. and saturated with HCl(g). The resulting solution was allowed to warm up to rt over 18 h. The mixture was concentrated in vacuo, re-dissolved in dry MeOH and (NH₄)₂ CO₃ (672.0 mg) was added, flask sealed and stirred for 18 at rt. The resulting suspension was filtered through Celite®, rinsed with dry MeOH, concentrated in vacuo to afford 997 mg of product (89% by HPLC); 100 mg of which was further purified via prep HPLC to afford 29 mg (100% purity by HPLC). M.p. 214-215° C. HRMS (NH₃ -CI) for C₂₃ H₂₆ N₄ O (M+H)⁺ calc. 375.217601, found 375.218487. ¹ H NMR (CD₃ OD) δppm 1.05 (qd, 1H, J=7.5 Hz, J=2.5 Hz), 1.25 (qd, 1H, J=7.5, J=2.5 Hz), 1.65 (bd, 1H, J=7.5 Hz), 1.76 (bd, 1H, J=7.5 Hz), 1.83 (m, 1H), 2.58 (d, 2H, J=6.0 Hz0, 2.63 (t, 1H, J=75 Hz), 3.07 (t, 1H, J=7.5 Hz), 4.03 (bd, 1H, J=7.5 Hz), 4.2 (bd, 1H, J=7.5 Hz), 5.21 (qd, 2H, J=7.5 Hz), 6.63 (s, 1H), 7.18 (m, 3H), 7.23 (m, 2H), 7.38 (s, 1H), 7.51 (d, 1H, J=5.0 Hz), 7.58 (d, 1H, J=5.0 Hz), 8.05 (s, 1H).

EXAMPLE 102

Preparation of 1-(4-benzylpiperidinecarbonyl)ethyl-5-amidinoindole

Methyl-5-cyanoindole-3-propionate. To a stirred solution of 5-cyanoindole (1.0 g, 7.0 mmol), K₂ CO₃ (0.966 g, 7.0 mmol) in acetonitrile was added 3-bromomethylpropionate (1.17 g, 7.0 mmol). The mixture was stirred at reflux for 18 h under a nitrogen atmosphere, cooled, diluted with H₂ O, extracted with ethyl acetate, dried with Na₂ SO₄, filtered and concentrated in vacuo to afford 1.59 g of product. ¹ H NMR (CD₃ OD) δppm 2.85 (t, 2H, J=6.6 Hz), 3.61 (s, 3H), 4.58 (t, 2H, J=6.6 Hz), 6.61 (s, 1H), 7.42, (m, 3H), 7.62 (d, 1H, J=8.4 Hz), 7.99 (s, 1H).

5-Cyanoindole-3-propionic acid. Methy-5-cyanoindole-3-propionate (200 mg) was saponified in MeOH (10 mL)/KOH (150 mg, 0.88 mmol) at rt for 18 h. The solution was concentrated in vacuo, dissolved in water and washed with chloroform. The acidic layer was acidified and extracted with ethyl acetate, dried with Na₂ SO₄, filtered and concentrated in vacuo to afford 188 mg of product. ¹ H NMR (CD₃ OD) δppm 2.83 (t, 2H, J=6.6Hz), 4.43 (t, 2H, J=6.6 Hz), 6.6 (nd,1H, J3.2 Hz), 7.42 (d, 2H, J=7.3 Hz), 7.43 (s, 1H), 7.61 (d, 1H, J=7.3 Hz), 7.99 (s, 1H); LRMS ESI (M+H)⁺ 215.

1-(4-Benzylpiperidinecarbonyl)ethyl-5-amidinoindole. Preparation follows the same last two steps of example 101. Afforded 156 mg of the TFA salt ¹ H NMR (DMSO-d₆) δppm 2.42 (m, 4H), 2.89 (m, 4H), 3.21 (d, 2H, J=5.0 Hz), 3.72 (bd, 1H, J=10.0 Hz), 4.12 (m,1H), 4.38 (bd, 1H, J=10 Hz), 4.51 (m, 2H), 6.62 (s, 1H), 7.1-7.31 (m, 5H), 7.62 (m,2H), 7.72 (d, 1H, J=6.0 Hz), 8.21 (bs, 1H); HRMS (M+H)⁺ for C₂₄ H₂₉ N₄ O calc. 389.234137, found 389.231258.

EXAMPLE 103

Preparation of 1-(4-(3-fluoro)benzylpiperidinecarbonyl)methyl-5-amidinoindole

4-(3-Fluorobenzyl)piperidine. To a stirred solution of 1-benzylpiperidin-4-one (0.99 mL, 5.34 mmol) in THF was added Ph₃ P═CH-(3-fluoro)phenyl (2.41 g, 5.34 mmol) at 0° C. under a nitrogen atmosphere. After stirring for 4 h at rt, the reaction was quenched with H₂ O, concentrated in vacuo and the residue was chromatographed on silica gel using 1:1 hexanes:ethyl acetate as the eluant to afford 313 mg of product. LRMS NH₃ -CI (M+H)⁺ 282. The product (330 mg) was hydrogenated in MeOH, 10% Pd/C (300 mg) and conc. HCl (5 mL) in a parr shaker at 50 psi for 18 h. The reaction was filtered through Celite® and the filtrate was concentrated in vacuo to afford 250 mg of the title compound. LRMS NH₃ -CI (M+H)⁺ 194.

1-(4-(3-Fluoro)benzylpepiridinocarbonyl)methyl-5-cyanoindole. Prepared as in example 101. LRMS ESI (M+H)⁺ 376.

1-(4-(3-Fluoro)benzylpepiridinocarbonyl)methyl-5-amidinoindole. Example 103 was prepared via the same method as example 101. HRMS FAB glycerol matrix for C₂₃ H₂₆ N₄ FO (M+H)⁺ calc. 393.209065, found 393.208858.

EXAMPLE 104

Preparation of 1-(1-(4-amidino)benzyl-N-(methylacetate)aminocarbonyl)methyl-5-amidinoindole

(4-Cyano)benzyl-N-(methylacetate) amine. α-Bromo-tolunitrile (2.0 g, 10.5 mmol) was dissolved in CHCl₃ and glycine methyl ester (2.64 g, 21.0 mmol) and triethyl amine (2.92 mL, 10.5 mmol) was added. The mixture was stirred for 18 h under nitrogen atmosphere, concentrated in vacuo and purified via silica gel column using 1:1 hexanes:ethyl acetate as the eluant to afford 1.07 g of the title compound (5.25 mmol). LRMS ESI (M+H)⁺ 205. ¹ H NMR (CDCl₃) δppm 3.42 (s, 2H), 3.78 (s, 3H), 3.91 (s, 2H), 7.42 (d, 2H, J=8.0 Hz), 7.62 (d, 2H, J=8.0 Hz).

1-(1-(4-Cyano)benzyl-N-(methylacetate)aminocarbonyl)methyl-5-cyanoindole. Compound was prepared using the same coupling procedure as in example 101. HRMS NH₃ -CI for C₂₃ H₂₀ N₄ O₃ (M+H)⁺ calc. 401.161366, found 401.159527.

1-(1-(4-Amidino)benzyl-N-(methylacetate)aminocarbonyl)methyl-5-amidinoindole. Prepared by the same Pinner conditions as example 101. LRMS ESI (M+2H)⁺² 218.

EXAMPLE 105

Preparation of Methyl 1-(4-benzylpiperidine-1-carbonyl)methyl-5-amidinoindole-3-propanoate

Methyl 1-(4-benzylpiperidine-1-carbonyl)methyl-5-cyanoindole-3-propanoate. 1-(4-Benzylpiperidine-1-carbonyl)-5-cyanoindole (1.0 g, 2.8 mmol) was dissolved in 20 mL of dry CH₂ Cl₂, cooled to 0° C. and oxalyl chloride (1.07 g, 8.4 mmol) was added. The reaction stirred for 3 h at rt. It was then concentrated in vacuo and dissolved in dry MeOH (20 mL) and stirred for 18 h. The resulting yellow solution was concentrated in vacuo and 1.0 g (2.3 mmol) was taken up in TFA (20 mL) at 0° C. and triethylsilane (535 mg, 4.6 mmol) was slowly added. The reaction stirred at 0° C. for 3 h and then it was concentrated in vacuo, dissolved in CH₂ Cl₂ and washed with sat. NaHCO₃, dried with sodium sulfate, filtered and concentrated. The resulting residue was chromatographed via silica gel using 7% MeOH/CHCl₃ as the eluant to afford 840 mg of the title compound. LRMS ESI (M+H)⁺ 430.

1-(4-Benzylpiperidine-1-carbonyl)methyl-3-methylacetate-5-amidinoindole. The amidine was prepared as in example 101. HRMS NH₃ -CI for C₂₆ H₃₄ N₄ O₃ (M+H)⁺ calc. 447.239616, found 447.241907.

EXAMPLE 106

Preparation of 1-((4-benzylpiperidinecarbonyl)methyl-(3-ethanehydroxyl)-5-amidinoindole

1-(4-Benzylpiperidine-1-carbonyl)methyl-3-ethanehydroxyl-5-cyanoindole. Methyl 1-acetyl-(4-benzylpiperidin-1-yl)-3-acetate-5-cyanoindole (100 mg, 0.233 mmol) was dissolved in ethanol and sodium borohydride (20 mg, 0.51 mmol) was added and the solution stirred at rt for 18 h. The reaction was concentrated in vacuo diluted with water and extracted with methylene chloride (3×), dried over sodium sulfate, filtered and concentrated in vacuo to afford 93.0 mg of the title compound. LRMS DCI-NH₃ (M+NH₄)⁺ 419.

1-(4-Benzylpiperidine-1-carbonyl)methyl-3-ethanehydroxyl-5-amidinoindole. The amidine was prepared as in example 101. HRMS NH₃ -CI for C₂₅ H₃₁ N₄ O₂ (M+H)⁺ calc. 419.244702, found 419.245383.

EXAMPLE 107

Preparation of 1-(4-benzylpiperidine-1-carbonyl)methyl-3-methylcarboxylic acid-5-amidinoindole

Methyl 1-acetyl-(4-benzylpiperidin-1-yl)-3-acetate-5-amidinoindole was hydrolyzed in TFA/H₂ O for 18 h. Purified via prep HPLC to afford the title compound. LRMS (M+H)⁺ 433.

EXAMPLE 108

Preparation of 1-(1-Benzylpiperidine-4-aminocarbonyl)methyl-5-amidinoindole

1-(1-Benzylpiperidine-4-aminocarbonyl)methyl-5-cyanoindole. To a stirred complex of N-1-methylenecarbohydroxy-5-cyanoindole (300 mg, 1.5 mmol) and DEC was added 4-amino-1 benzylpiperidine and triethylamine (0.209 mL, 1.5 mmol). The reaction was stirred at rt for 18 h. The volatiles were removed in vacuo and the residue was purified via silica gel using 1% MeOH/CH₂ Cl₂ as the eluant to afford 160 mg of product. HRMS NH₃ -CI for C₂₃ H₂₄ N₄ O (M+H)⁺ calc 373.204.204739, found 373.202837.

1-(1-Benzylpiperidine-4-aminocarbonyl)methyl-5-amidinoindole. The amidine was prepared as in example 101 to afford 96 mg of the title compound. HRMS NH₃ -CI calc. 390.229386, found 390.229386.

EXAMPLE 109

Preparation of 1-(4-benzoylpiperidinecarbonyl)methyl-5-amidinoindole

1-(4-Benzoylpiperidinecarbonyl)methyl-5-cyanoindole. Prepared as in example 108 except using 4-benzoylpiperidine. HRMS NH₃ -CI (M+H)⁺ for C₂₃ H₂₁ N₃ O₂ calc.372.171702, found 372.171620.

1-(4-Benzoylpiperidinecarbonyl)methyl-5-amidinoindole. The amidine was prepared using the same method as in example 101. HRMS (M+H)⁺ for C₂₃ H₂₄ N₄ O₃ calc. 389.197751, found 389.198109.

EXAMPLE 110

Preparation of 1-(4-(3-fluoro)benzylpiperazinecarbonyl)methyl-5-amidinoindole

1-(4-(3-Fluoro)benzylpiperazinecarbonyl)methyl-5-cyanoindole To a stirred solution of 1-acetyl-(1-piperazine)-5-cyanoindole (400 mg, 1.31 mmol), triethylamine (0.0.36 mL, 2.62 mmol) in diethyl ether was added 3-fluorobenzyl bromide (0.161 mL, 1.31 mmol) and stirred at room temperature under N₂ atmosphere for 18 h. The reaction quenced with water, extracted with ethyl acetate, dried with sodium sulfate, filtered and concentrated in vacuo to afford 438 mg product. LRMS (M+H)⁺ 377.

1-(4-(3-Fluoro)benzylpiperazinecarbonyl)methyl-5-amidinoindole. Prepared as in example 101. HRMS (M+H)⁺ for C₂₂ H₂₄ N₅ OF calc. 394.204314, found 394.204917.

EXAMPLE 111

Preparation of 1-(4-phenylbenzylaminocarbonyl)methyl-5-amidinoindole

1-(4-Phenylbenzylaminocarbonyl)methyl-5-cyanoindole. To a stirred complex of 1-acetic acid 5-cyanoindole (250 mg, 1.25 mmol) and DEC (239 mg,1.25 mmol) in methylene chloride was added 4-phenybenzylamine (228 mg, 1.25 mmol). After stirring at rt for 18 h under a nitrogen atmosphere, the reaction was concentrated in vacuo, dissolved in ethyl acetate, washed with 1 N HCl, sodium bicarbonate, and brine, dried with sodium sulfate, filtered and concentrated in vacuo to afford 215 mg of product. HRMS (M+H)⁺ calc. 366.260637, found 366.160323.

1-(4-Phenylbenzylamninocarbonyl)ethyl-5-amidinoindole. Prepared as in example 101. HRMS calc. 383.187187 found 383.189667.

EXAMPLE 112

Preparation of methyl 1-(4-benzylpiperidinecarbonyl)methyl-5-amidinoindole-3-propenoate

Methyl 1-(4-benzylpiperidinecarbonyl)methyl-5-cyanoindole-3-propenoate. To a stirred solution of DMF (15 mL) and POCl₃ (256 mg, 1.7 mmol) at 0° C. was added 1-(4-benzylpiperidinecarbonyl)methyl-5-cyanoindole (199 mg, 0.56 mmol). After stirring 3 h, the reaction was quenched with 2 N sodium hydroxide and stirred for 30 min. It was then extracted with chloroform, dried with sodium sulfate, filtered and concentrated in vacuo to afford product. LRMS (M+H)⁺ 386. The product was then refluxed in the presence of triphenyl phosphonium(methylenecarbomethoxy)ylide in THF under a nitrogen atmosphere for 18 h. The reaction was concentrated in vacuo and the residue purified via silica gel chromatography using 7%MeOH/CHCl₃ as the eluant to afford 140 mg of product.

Methyl 1-(4-benzylpiperidinecarbonyl)methyl-5-amidinoindole-3-propenoate. Prepared as in example 101. LRMS (M+H)⁺ 459.

EXAMPLE 113

Preparation of 1-(4-(2-fluoro)benzylpiperidinecarbonyl)methyl-5-amidinoindole

4-(2-Fluoro)benzylpiperidine. To a stirred solution of triphenylphosphonium-2-fluorobenzylbromide in dry THF at -78° C. was added n-buLi (2.5 M, 2.13 mL) and stirred for 30 min. To it was then added 1-benzyl-4-piperidinene (0.99 mL) and the mixture stirred at rt for 4 h. The reaction was quenched with water and concentrated in vacuo. The resulting residue was purified via silica gel chromatrography using 1:1 hexanes:ethyl acetate as the eluant to afford 313 mg. LRMS (M+H)⁺ 282. The product was hydrogenated in a parr shaker at 50 psi in MeOH (10 mL), 5.0 mL conc. HCl and 10%Pd/C (300 mg) for 18 h. The mixture was filterd through celite® and concentrated in vacuo to afford 250 mg of product. LRMS (M+H)⁺ 194.

1-(4-(2-Fluoro)benzylpiperidinecarbonyl)methyl-5-cyanoindole. Prepared by coupling 3-acetic acid-5-cyanoindole with 4-(2-fluoro)benzylpiperidine using the method described in example 101. LRMS (M+H)⁺ 376.

1-(4-(2-Fluoro)benzylpiperidinecarbonyl)methyl-5-amidinooindole. Prepared as in example 101. HRMS (M+H)⁺ calc. 393.209065, found 393.208858.

EXAMPLE 201

Preparation of 3-((4-cyclohexyl)phenylaminomethylcarbonyl)methyl-5-amidinoindole

Methyl 5-cyanoindole-3-acetate. To a stirred solution of 5-cyanoindole (10.0 g) in dry methylene chloride was added (3.0 eq, 61.43 mL) of oxalyl chloride. After stirring for 1 h under a nitrogen atmosphere at rt, the resulting precipitate was filtered and rinsed with diethyl ether. The solids were then taken up in dry MeOH and stirred for 1 h. At this time the solids were filtered and rinsed with MeOH and diethyl ether to afford 5.93 g of methyl α-ketoacetate 5-cyanoindole. LRMS (M+H)⁺ 229. Methyl α-ketoacetate (4.90 g) was dissolved in 50 mL trifluoro acetic acid at 0° C. and triethyl silane (5.0 g) was slowly added via a drop funnel (20 min.). It was then stirred at 0° C. for 3 h. The resulting yellow solution was concentrated in vacuo, neutralized with sodium bicarbonate, extracted with diethyl acetate, dried with magnesium sulfate filtered and concentrated in vacuo. Purification was accomplished via silica gel chromatography using 1% MeOH/CH₂ Cl₂ as the eluant to afford 2.48 g of product. LRMS (M+H)⁺ 232.

3-(5-Cyanoindole) acetic acid. The above ester was saponified in KOH/MeOH at rt for 18 h. The solution 3 was then concentrated in vacuo, dissolved in water, extracted with ethylacetate and the acidic layer was then acidified with 1 N HCl at 0° C. The resulting white solids were filtered and further dried under high vacuum to afford the product. M.p. 196.5-198.5; Calc. C66.00 H4.04 N13.99, found C65.71 H4.24 N13.94. ¹ H NMR (CD₃ OD) δppm 3.78 (s, 2H), 7.28 (s, 1H), 7.38 (d, 1H, J=8.6 Hz), 7.45 (d, 1H, J=8.6 Hz), 7.89 (s, 1H); LRMS (M+)⁺ 199.

3-(4-Cyclohexylphenylaminomethylcarbonyl)methyl-5-cyanoindole. To a stirred complex of the 5-cyanoindole acetic acid (312 mg, 1.5 mmol) and BOP reagent (1.03 g) in DMF was added 4-cyclohexylphenylaminomethyl. After heating at 50° C. under a nitrogen atmosphere for 18 h, the reaction was cooled to rt diluted with water and extracted with ethyl acetate, washed with 1 N HCl, sat. sodium bicarbonate, and brine, dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via chromatography using 100% ethyl acetate as the eluant to afford 210 mg of product. LRMS (M+H)⁺ 372.

3-((4-Cyclohexyl)phenylaminomethylcarbonyl)methyl-5-amidinoindole. Prepared as in example 101. HRMS (M+H)⁺ for C₂₄ H₂₉ N₄ O calc. 389.234137, found 389.232086.

EXAMPLE 202

Preparation of 3-(4-p-toluenesulfonyl-piperazinecarbonyl)methyl-5-amidinoindole

3-(4-Paratoluensulfonylpiperazinecarbonyl)methyl-5-cyanoindole. To a stirred solution of 3-(piperazinecarbonyl)methyl-5-cyanoindole hydrochloride (200 mg, 0.66 mmol) and triethylamine (134 mg, 185 μL) in chloroform was added toluenesulfonylchloride (126 mg, 0.66 mmol). After stirring for 18 h at rt under a nitrogen atmosphere, the reaction was quenched with water, extracted with chloroform, washed with 1 N HCl, sat sodium bicarbonate, and brine, dried with sodium sulfate, filtered and concentrated in vacuo to afford 237 mg of product. LRMS (M+H)⁺ 423.

3-(4-Paratoluensulfonylpiperazinecarbonyl)methyl-5-amidinoindole. Prepared as in example 101. HRMS (M+H)⁺ for C₂₂ H₂₆ N₅ O₃ S, calc. 440.174611, found 440.175637.

EXAMPLE 203

Preparation of 3-(4-(2-aminosulfonylphenyl)pyridine-2-aminocarbonyl)methyl-5-amidinoindol

3-(4-(2-Aminosulfonylphenyl)pyridine-2-aminocarbonyl)methyl-5-cyanoindole. To a stirred solution of 5-cyano-3-acetic acid indole (400 mg, 2.0 mmol), BOP (884 mg, 3.0 mmol) in DMF (15 mL) was added 4-(2-aminosulfonyl)phenyl-2-aminopyridine (912 mg, 3.0 mmol) and heated at 50° C. for 3 h. The reaction was diluted with water, extracted with ethyl acetate, washed with 10% HCl, sodium bicarbonate, brine, and water, dried with magnesium sulfate, filtered and concentrated in vacuo to afford 420 mg of product. LRMS 488. The t-butyl group was removed in TFA reflux for 1 h and the product purified via silica gel using 100% ethyl acetate as the eluant to afford 101 mg of product. LRMS 432.

3-(4-(2-Aminosulfonylphenyl)pyridine-2-aminocarbonyl)methyl-5-amidinoindole. Prepared as in example 101. HRMS (M+H)⁺ for C₂₂ H₂₂ N₅ O₃ S calc. 449.139586, found 449.139058.

EXAMPLE 204

Preparation of 3-(4-[2-tetrazole]phenyl)phenylaminocarbonyl)methyl-5-amidinoindole

3-(4-[2-Tetrazole]phenyl)phenylaminocarbonyl)methyl-5-cyanoindole. 5-cyanoindole-3-acetic acid was dissolved in DMF/CH₂ Cl₂, DEC (382 mg), and DMAP (10 mg) and the reaction mixture stirred for 15 min. 4-((2-Tetrazole)phenyl)aniline was added and the reactin mixture stirred for 2 h. The reaction was concentrated in vacuo, dissolved in ethylacetate and washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. Purification was done via silical gel using 1:1 hexanes:ethylacetate to afford 660 mg of product. The trityl group was cleaved in THF (30 mL) and 4 M HCl dioxane (0.988 mL) at rt for 18 h. It was then basified with NaOH to pH 11, washed with ether, acidified to pH 3 with 10% HCl and the precipitate was collected and dried under high vacuum to afford 250 mg of product. LRMS (M+H)⁺ 420.

3-(4-[2-Tetrazole]phenyl)phenylaminocarbonyl)methyl-5-amidinoindole. Prepared as in example 101. HRMS for C₂₃ H₂₀ N₈ O (M+H)⁺ calc. 437.183833, found 437.186710.

EXAMPLE 205

Preparation of 3-(4-biphenylaminocarbonyl)methyl-5-amidinoindole

The title compound was prepared as in example 101. HRMS (M+H)⁺ for C₂₃ H₂₀ N₄ O calc. 369.172173, found 369.171537.

EXAMPLE 206

Preparation of 3-(4-(phenylmethylsulfonyl)piperazinecarbonyl)methyl-5-amidinoindole

The title compound was prepared as in example 101. HRMS (M+H)⁺ C₂₂ H₂₅ N₅ O₃ S calc. 440.176204, found 440.175637.

EXAMPLE 207

Preparation of 3-(4-cyclohexylphenylaminocarbonyl)methyl-5-amidinoindole

The title compound was prepared as in example 101. HRMS (M+H)⁺ C₂₃ H₂₆ N₄ O calc. 375.218732. found 375.218487.

EXAMPLE 208

Preparation of 3-(4-benzylpiperazinecarbonyl)methyl-5-amidinoindole

The title compound was prepared as in example 101. HRMS (M+H)⁺ for C₂₂ H₂₅ N₅ O calc. 376.213722, found 376.213736.

EXAMPLE 209

Preparation of 3-(3-amidinobenzylamino(methylcarbonylmethoxy)carbonyl)methyl-5-amidinoindole

The title compound was prepared as in example 101. HRMS cal. 435.214464, found 435.216822.

EXAMPLE 210

Preparation of 1-methyl-3-(4-amidinobenzylamino(methylcarbonylmethoxy)carbonyl)methyl-5-amidinoindole

The title compound was prepared as in example 101. HRMS calc.435.214464, found 435.213247.

EXAMPLE 211

Preparation of 1-methyl-3-(4-[2-aminosulfonyl]phenylbenzylaminocarbonyl)methyl-5-amidinoindole

The title compound was prepared as in example 201. LRMS 476, m.p. 231° C.

EXAMPLE 212

Preparation of 1-methyl-3-(4-phenylbenzylaminocarbonyl)methyl-5-amidinoindole

The title compound was prepared as in example 201. HRMS calc. 397.202837, found 397.204520.

EXAMPLE 213

Preparation of 1-methyl-3-(4-phenylpiperazinecarbonyl)methyl-5-amidinoindole

The title compound was prepared as in example 201. HRMS calc. 389.234137, found 389.234635.

EXAMPLE 214

Preparation of 3-(4-[2-aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-amidinoindole

The title compound was prepared as in example 203. HRMS calc.448.144337 found 448.143656.

EXAMPLE 215

Preparation of 3-(1-benzylpiperidine-4-aminocarbonyl)methyl-5-amidinoindole

The title compound was prepared as in example 201. HRMS calc. 390.229386, found 390.230305.

EXAMPLE 216

Preparation of 3-(4-phenylpiperazinecarbonyl)methyl-5-amidinoindole

The title compound was prepared as in example 201. HRMS calc. 362.198086, found 362.197315.

EXAMPLE 217

Preparation of 3-(4-benzylpiperidinecarbonyl)methyl-5-amidinoindole

The title compound was prepared as in example 201. HRMS calc. 374.210662 found 374.210386.

EXAMPLE 218

Preparation of 1-methyl-3-(5-(2-aminosulfonyl)phenylpyridine-2-aminocarbonyl)methyl-5-amidinoindole

The title compound was prepared as in example 201. HRMS calc. 463.155236, found 463.155236.

EXAMPLE 219

Preparation of 3-(2-bromo-4-(2-aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-cyanoindole

A solution of 3-{2-bromo-4-(2-aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-cyanoindoline (1.2378 mmol, 0.7 g) in anhydrous methyl acetate (15 mL) and anhydrous methanol (0.5 mL, 10.0 eq) was saturated with dry hydrogen chloride gas at -20° C. for 20 min. The reaction mixture was stoppered tightly and left at ambient temperature for 18 h. This reaction mixture was evaporated and pumped on for several hours to remove any residual HCl. To this imidate in anhydrous methanol (15 mL) was added ammonium carbonate (1.189 g, 10.0 eq.). This reaction mixture was allowed to stir at ambient temperature for 24 h. This final reaction mixture was evaporated and purified by HPLC on a C-18 column eluted with solvent mixture A (water:TFA 99.95:0.05) and solvent mixture B (acetonitrile:TFA 99.95:0.05) using a gradient starting with A at 80% and changing to B at 100% over 60 min. After lyophylization, 0.122 g of pure product (15%) was obtained; HRMS (M+H)⁺ calc. 526.054848, found 526.053791 for o-Br compound.

EXAMPLE 220

Preparation of 3-(2-methyl-4-(2-aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-methylamino indole

To the solution of 3-{2-methyl-4-(2-aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-cyano indole (0.5992 mmol, 0.3 g) in absolute ethanol:TFA 4:6 was added palladium hydroxide on carbon (0.06 g, 20% weight equivalent of starting material used). This reaction mixture was stirred under house vacuum for 10 minutes at ambient temperature to remove oxygen. Then subjected to 1 atm H₂ via balloon method for 3 h. The reaction mixture was filtered through celite to remove catalyst and washed with ethanol (20 mL). The filtrate was evaporated to give the desired product with t-butyl sulfonamide. This product was treated with trifluoroacetic acid at 55° C. for 2 h for deprotection of sulfonamide. The reaction mixture was evaporated and purified by HPLC on a C-18 column eluted with solvent mixture A (water:TFA 99.95:0.05) and solvent mixture B (acetonitrile:TFA 99.95:0.05) using a gradient starting with A at 80% and changing to B at 100% over 60 min. to give 10.0 mg of pure product (3%, poor yield due to poor solubility); HRMS (M+H)⁺ calc. 449.164738, found 449.165207.

EXAMPLE 221

Preparation of 3-{2-fluoro-4-(2-aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-amidinoindole

The titled compound was prepared as in Example 203. HRMS (NH₃ -CI/DEP) (M+H)⁺ for C₂₃ H₂₁ N₅ SO₃ F calculated 466.134915; found 466.133832.

EXAMPLE 222

Preparation of 3-{2-chloro-4-(2-aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-cyanoindole

The titled compound was prepared as in Example 203. HRMS for C₂₅ H₂₁ N₅ SO₃ Cl (M+H)⁺ calc. 482.105364; found 482.103835.

EXAMPLE 223

Preparation of 3-{2-iodo-4-(2-aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-cyanoindole

The titled compound was prepared as in Example 203. HRMS for C₂₃ H₂₁ IN₅ O₃ S (M+H)⁺ calc. 574.040989; found 574.042800.

EXAMPLE 224

Preparation of 3-{2-methyl-4-(2-aminosulfonyl)phenylphenylaminocarbonyl)methyl-5-amidinoindole

The titled compound was prepared as in Example 203. HRMS for C₂₄ H₂₄ N₅ O₃ S (M+H)⁺ calc. 462.159987; found 462.158553.

EXAMPLE 225

Preparation of 3-{2-methyl-4-(2-(t-butylaminosulfonyl))phenylphenylaminocarbonyl)methyl-5-amidinoindole

The titled compound was prepared as in Example 203. HRMS for C₂₈ H₃₂ N₅ O₃ S (M+H)⁺ calc.518.222587; found 518.221998.

EXAMPLE 226

Preparation of 3-{4-(2-aminosulfonyl)phenyl)phenylaminocarbonylmethyl-α-(methylcarboxy methyl ether)-5-amidinoindole

The titled compound (racemic) was prepared as in Example 203. HRMS for C₂₆ H₂₅ N₅ O₅ S (M+H)⁺ calc 520.166599; found 520.165466.

EXAMPLE 227

Preparation of 3-{4-(2-aminosulfonyl)phenyl)phenylaminocarbonylmethyl-α-(benzyl)-5-amidinoindole

The titled compound (racemic) was prepared as in Example 203. HRMS for C₃₀ H₂₉ N₅ O₃ S (M+H)⁺ calc. 538.191287; found 538.191263.

EXAMPLE 228

Preparation of 3-{4-(2-trifluoromethyl)phenyl)pyrid-2-ylaminocarbonylmethyl-5-amidinoindole

The titled compound was prepared as in Example 203. HRMS for C₂₃ H₂₀ N₅ O₁ F₃ (M+H)⁺ 438.154170; found 438.152166.

EXAMPLE 229

Preparation of 3-{4-(2-ethylaminosulfonyl)phenyl)phenylaminocarbonylmethyl-5-amidinoindole

The titled compound was prepared as in Example 203. HRMS for C₂₆ H₂₇ N₅ O₃ S₁ (M+H)⁺ calc. 476.175637; found 476.175892.

EXAMPLE 230

Preparation of 3-{4-(2-propylaminosulfonyl)phenyl)phenyl}aminocarbonylmethyl-5-amidinoindole

The titled compound was prepared as in Example 203. HRMS for C₂₆ H₂₇ N₅ O₃ S (M+H)⁺ calc. 490.191287; found 490.190996.

EXAMPLE 231

Preparation of 2-methyl-3-{2-iodo-4-(2-aminosulfonyl)phenyl)phenyl}aminocarbonylmethyl-5-amidinoindole

The titled compound was prepared as in Example 203. HRMS for C₂₄ H₂₃ IN₅ O₃ S₁ (M+H)⁺ calc. 558.056639; found 558.057057.

EXAMPLE 232

Preparation of 2-methyl-3-{4-(2-aminosulfonyl)phenyl)phenyl}aminocarbonylmethyl-5-amidinoindole

The titled compound was prepared as in Example 203. LRMS for C₂₄ H₂₃ N₅ O₃ S₁ (M+H)⁺ 462.

EXAMPLE 233

Preparation of 3-{4-(2-aminosulfonyl)phenyl)phenyl}-N-methylaminocarbonylmethyl-5-amidinoindole

The titled compound was prepared as in Example 203. LRMS for C₂₄ H₂₄ N₅ O₃ S₁ (M+H)⁺ 462.

EXAMPLE 234

Preparation of 2-methyl-3-{4-(2-t-butylaminosulfonyl)phenyl)phenyl}aminocarbonylmethyl-5-methoxyindole

The titled compound was prepared as in Example 203. LRMS for C₂₈ H₃₁ N₃ O₄ S₁ (M+H)⁺ 506.

EXAMPLE 235

Preparation of 3-{4-(2-N-methylaminosulfonyl)phenyl)phenyl}-N-methylaminocarbonylmethyl-5-amidinoindole

The titled compound was prepared as in Example 203. HRMS for C₂₄ H₂₃ N₅ O₃ S (M+H)⁺ cacl. 462.159987; found 462.159054.

EXAMPLE 236

Preparation of 3-{4-(2-(n-butylaminosulfonyl)phenylphenylaminocarbonyl)methyl-5-cyanoindoline

To a solution of 3-acetic acid indoline (0.001 mol, 0.2 g) [or indoline acid (0.001 mol, 0.202 g)] in anhydrous acetonitrile (10 mL) was added thionyl chloride (0.3 mL, 4.0 eq.) [for indoline, 1.0 M HCl in ethyl ether (0.05 mL, 1.0 eq.) was added before thionyl chloride]. This reaction mixture was warmed up at 50° C. for 10 min. then allowed to cool to ambient temperature and stirred for 2 h. The solvent and extra thionyl chloride were removed in vacuo and the residue was pumped on for several hours for further dry. To this dried residue was added a mixture of A-B (0.338 g, 1.0 eq.) and triethyl amine (0.14 mL, 1.0 eq.; 2.0 eq. for HCl salt) in anhydrous methylene chloride (10 mL). This reaction mixture was allowed to stir at ambient temperature for 2 h. The reaction mixture was evaporated and purified by flash chromatography on a silica gel column (50 g) eluted with 3:1 hexane:ethyl acetate to give 0.4 g of pure product with n-butyl sulfonamide (51%).

EXAMPLE 237

Preparation of 3-{4-(2-(n-propylaminosulfonyl)phenylphenylaminocarbonyl)methyl-5-amidinoindoline

The titled compound was prepared as in Example 203. HRMS for C₂₆ H₃₀ N₅ SO₃ (M+H)⁺ calc. 492.206937; found 492.207667.

EXAMPLE 238

Preparation of (-)-3-{4-(2-aminosulfonyl)phenyl)pyrid-2-ylaminocarbonylmethyl-5-amidinoindoline

The titled compound was prepared as in Example 203. HRMS for C₂₂ H₂₄ N₆ O₃ S₁ (M+H)⁺ calc.451.155236; found 451.154317.

EXAMPLE 239

Preparation of 3-{4-(2-aminosulfonyl)phenyl)pyrid-2-ylaminocarbonylmethyl-5-amidinoindoline

The titled compound (racemic) was prepared as in Example 203. HRMS for C₂₂ H₂₄ N₆ O₃ S₁ (M+H)⁺ calc. 451.155236; found 451.154317.

EXAMPLE 240

Preparation of 3-{4-(2-dimethylaminosulfonyl)phenyl)phenylaminocarbonylmethyl-5-amidinoindoline

The titled compound (racemic) was prepared as in Example 203. HRMS for C₂₅ H₂₆ N₅ O₃ S₁ (M+H)⁺ calc. 450.159987; found 450.159435.

EXAMPLE 241

Preparation of (+)-3-{4-(2-t-butylaminosulfonyl)phenyl)pyrid-2-ylaminocarbonylmethyl-5-amidinoindoline

The titled compound was prepared as in Example 203. HRMS for C₂₆ H₃₀ N₆ O₃ S₁ (M+H)⁺ calc. 507.217836; found 507.217901. 98%ee; rotation (+) 19.23.

EXAMPLE 242

Preparation of (-)-3-{4-(2-t-butylaminosulfonyl)phenyl)pyrid-2-ylaminocarbonylmethyl-5-amidinoindoline

The titled compound was prepared as in Example 203. HRMS for C₂₆ H₃₀ N₆ O₃ S₁ (M+H)⁺ calc.507.217836; found 507.217678. 98%ee; rotaion -16.28.

EXAMPLE 243

Preparation of 3-{4-(2-aminosulfonyl)phenyl)pyrid-2-yl)aminocarbonylmethyl-5-aminocarboxyindoline

The titled compound (racemic) was prepared as in Example 203. HRMS for C₂₂ H₂₃ N₆ O₃ S₁ (M+H)⁺ calc. 451.1552036; found 451.154691.

EXAMPLE 244

Preparation of 3-{4-(2-t-butylaminosulfonyl)phenyl)phenyl}aminocarbonylmethyl-5-amidinoindoline

The titled compound was prepared as in Example 203. LRMS for C₂₇ H₃₁ N₅ O₃ S₁ (M+H)⁺ calc.506.3; found 506.4.

EXAMPLE 245

Preparation of 3-{4-(2-t-butylaminosulfonyl)phenyl)pyrid-2-yl}aminocarbonylmethyl-5-amidinoindoline

The titled compound (racemic) was prepared as in Example 203. LRMS for C₂₆ H₃₀ N₆ O₃ S₁ (M+H)⁺ calc.507.3; found 507.4.

EXAMPLE 246

Preparation of 3-{4-(2-aminosulfonyl)phenyl)pyrid-2-ylaminocarbonylmethyl-6-amidinoindazole

The titled compound was prepared as in Example 203. HRMS for C₂₁ H₂₁ N₇ O₃ S₁ (M+H)⁺ calc. 450.134835; found 450.134725.

EXAMPLE 247

Preparation of 3-{4-(2-aminosulfonyl)phenyl)phenyl aminocarbonylmethyl-6-amidinoindazole

The titled compound was prepared as in Example 203. HRMS for C₂₂ H₂₂ N₆ O₃ S₁ (M+H)⁺ calc. 449.139586; found 449.138515.

EXAMPLE 248

Preparation of 3-{4-(2-t-butyl aminosulfonyl)phenyl)pyrid-2-ylaminocarbonylmethyl-6-amidinoindazole

The titled compound was prepared as in Example 203. HRMS for C₂₅ H₂₉ N₇ O₃ S₁ (M+H)⁺ calc.450.134835; 450.134725

EXAMPLE 249

Preparation of 3-{4-(2-t-butylaminosulfonyl)phenyl)phenyl aminocarbonylmethyl-6-amidinoindazole

The titled compound was prepared as in Example 203. HRMS for C₂₆ H₃₀ N₆ O₃ S₁ (M+H)⁺ calc.505.202186; found 505.202631.

                  TABLE 5                                                          ______________________________________                                           #STR34##                                                                        -       Am.                       MS (100%) or                                Ex Pos. A B HRMS                                                             ______________________________________                                         1      a + b   phenethyl   3-amidino                                                                              204(M+2H).sup.2+                              2 b phenethyl 3-amidino 204.2(M+2H).sup.2+                                     3 a phenethyl 3-amidino 204.2(M+2H).sup.2+                                     4 a + b phenethyl 4-amidino 407.2200                                           5 b phenethyl 4-amidino 204(M+2H).sup.2+                                       6 a phenethyl 4-amidino 204(M+2H).sup.2+                                       7 a + b phenyl-CH═ 4-amidino 196.2(M+2H).sup.2+                            8 a + b phenyl 4-amidino 197(M+2H).sup.2+                                    ______________________________________                                    

                  TABLE 6a                                                         ______________________________________                                           #STR35##                                                                        -     Am.                             MS (100%)                               Ex Pos. Z A B or HRMS                                                        ______________________________________                                         51   a      C(O)     phenyl  4-phenyl  355.1554                                  52 b C(O) phenyl 4-phenyl 355.1559                                             53 a C(O) phenyl 4-(3-NH.sub.2)phenyl 370                                           (M+H).sup.+                                                               54 b C(O) phenyl 4-(3-NH.sub.2)phenyl 370                                           (M+H).sup.+                                                               55 a C(O) phenyl 4-(4-F)phenyl 373.1481                                        56 a C(O) phenyl 4-(4-CHO)phenyl 383.1531                                      57 a C(O) phenyl 4-(2- 434.1303                                                    NH.sub.2 SO.sub.2)phenyl                                                   58 a C(O) phenyl 4-(2-tBuNHSO.sub.2)                                               phenyl                                                                     59 a C(O) phenyl 4-(2-tetrazolyl) 423.1686                                         phenyl                                                                     60 a C(O)NH phenyl 4-(2- 449.1414                                                  NH.sub.2 SO.sub.2)phenyl                                                   61 b C(O)NH phenyl 4-(2- 449.1401                                                  NH.sub.2 SO.sub.2)phenyl                                                   62 a + b C(O) 1-piperidine 4-benzyl 376.2118                                   63 b C(O) 1-piperidine 4-benzyl 376.2130                                       64 a C(O) phenyl 4-(2- 449.1393                                                    NH.sub.2 SO.sub.2)phenyl                                                    65* 6- C(O) phenyl 4-(2-tBuNHSO.sub.2) 436                                     aza   phenyl                                                                ______________________________________                                          *Ex. 65 contains the CH.sub.2 -ZA-B group at the 2position.              

                  TABLE 6b                                                         ______________________________________                                           #STR36##                                                                       Ex     Z'         A      B            HRMS                                   ______________________________________                                          65* CH.sub.2 C(O)                                                                             phenyl   4-(2-tBuNHSO.sub.2)phenyl                                                                   464.1756                                   66 SCH.sub.2 C(O)NH phenyl 4-(2-tBuNHSO.sub.2)phenyl 496.1477                  67 SCH.sub.2 C(O)NH phenyl 4-(2-NH.sub.2 SO.sub.2)phenyl 440.0831            ______________________________________                                    

                  TABLE 7                                                          ______________________________________                                           #STR37##                                                                        -                                       MS or                                 Ex R.sup.1 Z' A B HRMS                                                       ______________________________________                                         101  H         C(O)      1-piperidine                                                                           4-benzyl                                                                               375.218                                 102 H CH.sub.2 C(O) 1-piperidine 4-benzyl 389.231                              103 H C(O) 1-piperidine 4- 393.209                                                 (3-F)benzyl                                                                104 H C(O)N(CH.sub.2 benzyl 4-amidino 218                                        CO.sub.2 CH.sub.3)                                                           105 CH.sub.2 -- C(O) 1-piperidine 4-benzyl 447.242                              CO.sub.2 Me                                                                   106 CH.sub.2 -- C(O) 1-piperidine 4-benzyl 419.245                              CH.sub.2 OH                                                                   107 CH.sub.2 -- C(O) 1-piperidine 4-benzyl 433                                  CO.sub.2 H                                                                    108 H C(O)NH 4-piperidine 1-benzyl 390.229                                     109 H C(O) 1-piperidine 4-benzoyl 389.198                                      110 H C(O) 1-piperazinyl 4- 394.205                                                (3-F)benzyl                                                                111 H C(O)NH benzyl 4-phenyl 383.190                                           112 CH═CH-- C(O) piperidine 4-benzyl 459                                    CO.sub.2 Me                                                                   113 H C(O) piperidine 4- 393.209                                                   (2-F)benzyl                                                              ______________________________________                                    

                  TABLE 8a*                                                        ______________________________________                                           #STR38##                                                                        -                                         MS or                               Ex C R.sup.1 Z A B HRMS                                                      ______________________________________                                         201  Am      H     C(O)-- phenyl  4-cyclohexyl                                                                            389.232                                  CH.sub.2 NH                                                                 202 Am H C(O) 1- 4-p-toluene- 440.176                                              piperazinyl sulfonyl                                                       203 Am H C(O)NH 2-pyridyl 4-(2-amino- 449.139                                       sulfonyl)                                                                      phenyl                                                                    204 Am H C(O)NH 1-phenyl 4-(2-tetrazol-5- 437.187                                   yl)phenyl                                                                 205 Am H C(O)NH 1-phenyl 4-phenyl 369.171                                      206 Am H C(O) 1- 4-phenyl- 440.176                                                 piperazinyl methylsulfonyl                                                 207 Am H C(O)NH 1-phenyl 4-cyclohexyl 375.218                                  208 Am H C(O) 1- 4-benzyl 376.214                                                  piperazinyl                                                                209 Am Me C(O)N-- benzyl 3-amidino 435.217                                        (CH.sub.2 CO.sub.2                                                             CH.sub.3)                                                                   210 Am Me C(O)N-- benzyl 4-amidino 435.213                                        (CH.sub.2 CO.sub.2                                                             CH.sub.3)                                                                   211 Am Me C(O)NH benzyl 4-(2- 476                                                   aminosulfonyl)                                                                 phenyl                                                                    212 Am Me C(O)NH benzyl 4-phenyl 397.205                                       213 Am Me C(O)CH.sub.2 1- 4-benzyl 389.235                                         piperazinyl                                                                214 Am H C(O)NH phenyl 4-(2- 448.144                                                aminosulfonyl)                                                                 phenyl                                                                    215 Am H C(O) 4- 1-benzyl 390.230                                                  piperidinyl                                                                216 Am H C(O) 1- 4-phenyl 362.197                                                  piperazinyl                                                                217 Am H C(O) 1- 4-benzyl 374.210                                                  piperidinyl                                                                218 Am Me C(O)NH 2-pyridyl 5-(2- 463.155                                            aminosulfonyl)                                                                 phenyl                                                                    219 CN H C(O)NH 2-Br-phenyl 4-(2- 526.054                                           aminosulfonyl)                                                                 phenyl                                                                    220 CH.sub.3 -- H C(O)NH 2-Me-phenyl 4-(2- 449.164                              NH    aminosulfonyl)                                                               phenyl                                                                    221 Am H C(O)NH 2-F-phenyl 4-(2- 466.134                                            aminosulfonyl)                                                                 phenyl                                                                    222 CN H C(O)NH 2-Cl-phenyl 4-(2- 482.104                                           aminosulfonyl)                                                                 phenyl                                                                    223 CN H C(O)NH 2-I-phenyl 4-(2- 574.043                                            aminosulfonyl)                                                                 phenyl                                                                    224 Am H C(O)NH 2-Me-phenyl 4-(2- 462.156                                           aminosulfonyl)                                                                 phenyl                                                                    225 Am H C(O)NH 2-Me-phenyl 4-(2-t-Bu- 518.222                                      aminosulfonyl)                                                                 phenyl                                                                    226 Am H (CH.sub.3 O-- phenyl 4-(2- 520.165                                       C(O)--  aminosulfonyl)                                                         CH.sub.2)CH  phenyl                                                         227 Am H (phenyl- phenyl 4-(2- 538.191                                            CH.sub.2)CH  aminosulfonyl)                                                      phenyl                                                                    228 Am H C(O)NH 2-pyridyl 4-(2-CF.sub.3 - 438.152                                   phenyl)                                                                   229 Am H C(O)NH phenyl 4-(2- 476.176                                                ethylamino-                                                                    sulfonyl)phenyl                                                           230 Am H C(O)NH phenyl 4-(2- 490.191                                                propylamino-                                                                   sulfonyl)phenyl                                                           231 Am H C(O)NH 2-I-phenyl 4-(2- 558.057                                          (R.sup.1 ═2--  aminosulfonyl)                                              methyl)  phenyl                                                             232 Am H C(O)NH phenyl 4-(2- 462                                                  (R.sup.1 ═2--  aminosulfonyl)                                              methyl)  phenyl                                                             233 Am H C(O)-- phenyl 4-(2- 462                                                  NCH.sub.3  aminosulfonyl)                                                        phenyl                                                                    234 CH.sub.3 O H C(O)NH phenyl 4-(2-t-Bu- 506                                     (R.sup.1 ═2--  aminosulfonyl)                                              methyl)  phenyl                                                             235 Am H C(O)-- phenyl 4-(2- 462.160                                              NCH.sub.3  methylamino-                                                          sulfonyl)phenyl                                                         ______________________________________                                          *For all Examples, but 226 and 277, n = 1. For Examples 226 and 227, n =       0.                                                                       

                  TABLE 8b                                                         ______________________________________                                           #STR39##                                                                        -                                         MS or                               Ex D R.sup.1 Z A B HRMS                                                      ______________________________________                                         236  CN      H     C(O)NH phenyl 4-(2-n-Bu-                                           aminosulfonyl)                                                                 phenyl                                                                    237 Am H C(O)NH phenyl 4-(2-propyl- 492.208                                         amino-                                                                         sulfonyl)phenyl                                                           238 Am H C(O)NH 2-pyridyl 4-(2-amino- 451.154                                  (-)     sulfonyl)phenyl                                                        239 Am H C(O)NH 2-pyridyl 4-(2-amino- 451.155                                       sulfonyl)phenyl                                                           240 Am H C(O)NH phenyl 4-(2-N,N- 450.160                                            dimethylamino-                                                                 sulfonyl)phenyl                                                           241 Am H C(O)NH 2-pyridyl 4-(2-t-Bu-amino- 507.218                             (+)     sulfonyl)phenyl                                                        242 Am H C(O)NH 2-pyridyl 4-(2-t-Bu-amino- 507.218                             (-)     sulfonyl)phenyl                                                        243 NH.sub.2 -- H C(O)NH 2-pyridyl 4-(2-amino- 451.154                          C(O)    sulfonyl)phenyl                                                       244 Am H C(O)NH phenyl 4-(2-t-Bu-amino- 506.4                                       sulfonyl)phenyl                                                           245 Am H C(O)NH 2-pyridyl 4-(2-t-Bu-amino- 507.4                                    sulfonyl)phenyl                                                         ______________________________________                                    

                  TABLE 8c                                                         ______________________________________                                           #STR40##                                                                        -                                         MS or                               Ex D R.sup.1 Z A B HRMS                                                      ______________________________________                                         246   Am     H     C(O)NH 2-pyridyl                                                                             4-(2-     450.135                                    aminosulfonyl)                                                                 phenyl                                                                    247 Am H C(O)NH phenyl 4-(2- 449.139                                                aminosulfonyl)                                                                 phenyl                                                                    248 Am H C(O)NH 2-pyridyl 4-(2-t-Bu-amino- 450.135                                  sulfonyl)phenyl                                                           249 Am H C(O)NH phenyl 4-(2-t-Bu-amino- 505.203                                     sulfonyl)phenyl                                                         ______________________________________                                    

                  TABLE 9                                                          ______________________________________                                           #STR41##                                                                       Ex     n     Z              A-B                                              ______________________________________                                         301  1     C(O)             4-(2-                                                   aminosulfonylphenyl)phenyl                                                  302 1 C(O) 4-(2-aminosulfonylphenyl)-2-                                           pyridyl                                                                     303 1 C(O) 4-(2-methylaminosulfonyl-                                              phenyl)phenyl                                                               304 1 C(O) 4-(2-ethylaminosulfonyl-                                               phenyl)-2-pyridyl                                                           305 1 C(O) 2-aminosulfonyl-4-                                                     cyclohexylphenyl                                                            306 1 C(O) 3-aminosulfonyl-4-t-butyl-2-                                           pyridyl                                                                     307 1 C(O) 2-(5-indazol-5-yl)furanyl                                           308 1 C(O) 2-(5-indazol-6-yl)thienyl                                           309 1 C(O) 4-(2-tetrazolylphenyl)phenyl                                        310 1 C(O)NH 4-(2-                                                                aminosulfonylphenyl)phenyl                                                  311 1 C(O)NH 4-(2-aminosulfonylphenyl)-2-                                         pyridyl                                                                     312 1 C(O)NH 4-(2-methylaminosulfonyl-                                            phenyl)phenyl                                                               313 1 C(O)NH 4-(2-ethylaminosulfonyl-                                             phenyl)-2-pyridyl                                                           314 1 C(O)NH 2-aminosulfonyl-4-                                                   cyclohexylphenyl                                                            315 1 C(O)NH 3-aminosulfonyl-4-t-butyl-2-                                         pyridyl                                                                     316 1 C(O)NH 2-(5-indazol-5-yl)furanyl                                         317 1 C(O)NH 2-(5-indazol-6-yl)thienyl                                         318 1 C(O)NH 4-(2-tetrazolylphenyl)phenyl                                      319 1 NHC(O) 4-(2-                                                                aminosulfonylphenyl)phenyl                                                  320 1 NHC(O) 4-(2-aminosulfonylphenyl)-2-                                         pyridyl                                                                     321 1 NHC(O) 4-(2-methylaminosulfonyl-                                            phenyl)phenyl                                                               322 1 NHC(O) 4-(2-ethylaminosulfonyl-                                             phenyl)-2-pyridyl                                                           323 1 NHC(O) 2-aminosulfonyl-4-                                                   cyclohexylphenyl                                                            324 1 NHC(O) 3-aminosulfonyl-4-t-butyl-2-                                         pyridyl                                                                     325 1 NHC(O) 2-(5-indazol-5-yl)furanyl                                         326 1 NHC(O) 2-(5-indazol-6-yl)thienyl                                         327 1 NHC(O) 4-(2-tetrazolylphenyl)phenyl                                      328 1 SO.sub.2 NH 4-(2-                                                           aminosulfonylphenyl)phenyl                                                  329 1 SO.sub.2 NH 4-(2-aminosulfonylphenyl)-2-                                    pyridyl                                                                     330 1 SO.sub.2 NH 4-(2-methylaminosulfonyl-                                       phenyl)phenyl                                                               331 1 SO.sub.2 NH 4-(2-ethylaminosulfonyl-                                        phenyl)-2-pyridyl                                                           332 1 SO.sub.2 NH 2-aminosulfonyl-4-                                              cyclohexylphenyl                                                            333 1 SO.sub.2 NH 3-aminosulfonyl-4-t-butyl-2-                                    pyridyl                                                                     334 1 SO.sub.2 NH 2-(5-indazol-5-yl)furanyl                                    335 1 SO.sub.2 NH 2-(5-indazol-6-yl)thienyl                                    336 1 SO.sub.2 NH 4-(2-tetrazolylphenyl)phenyl                                 337 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-                                        aminosulfonylphenyl)phenyl                                                  338 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-aminosulfonylphenyl)-2-                                            pyridyl                                          339 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-methylaminosulfonyl-                    phenyl)phenyl                                                               340 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-ethylaminosulfonyl-                     phenyl)-2-pyridyl                                                           341 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-aminosulfonyl-4-                           cyclohexylphenyl                                                            342 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 3-aminosulfonyl-4-t-butyl-2-                                            pyridyl                                          343 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-(5-indazol-5-yl)furanyl                 344 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-(5-indazol-6-yl)thienyl                 345 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-tetrazolylphenyl)phenyl                                         346 0 CH(CH.sub.2 - 4-(2-                             tetrazolyl)C(O)NH aminosulfonylphenyl)phenyl                                 347 0 CH(CH.sub.2 - 4-(2-aminosulfonylphenyl)-2-                                 tetrazolyl)C(O)NH pyridyl                                                    348 0 CH(CH.sub.2 - 4-(2-methylaminosulfonyl-                                    tetrazolyl)C(O)NH phenyl)phenyl                                              349 0 CH(CH.sub.2 - 4-(2-ethylaminosulfonyl-                                     tetrazolyl)C(O)NH phenyl)-2-pyridyl                                          350 0 CH(CH.sub.2 - 2-aminosulfonyl-4-                                           tetrazolyl)C(O)NH cyclohexylphenyl                                           351 0 CH(CH.sub.2 - 3-aminosulfonyl-4-t-butyl-2-                                 tetrazolyl)C(O)NH pyridyl                                                    352 0 CH(CH.sub.2 - 2-(5-indazol-5-yl)furanyl                                    tetrazolyl)C(O)NH                                                            353 0 CH(CH.sub.2 - 2-(5-indazol-6-yl)thienyl                                    tetrazolyl)C(O)NH                                                            354 0 CH(CH.sub.2 - 4-(2-tetrazolylphenyl)phenyl                                 tetrazolyl)C(O)NH                                                          ______________________________________                                    

                  TABLE 10                                                         ______________________________________                                           #STR42##                                                                       Ex     n     Z              A-B                                              ______________________________________                                         401  1     C(O)             4-(2-                                                   aminosulfonylphenyl)phenyl                                                  402 1 C(O) 4-(2-aminosulfonylphenyl)-2-                                           pyridyl                                                                     403 1 C(O) 4-(2-methylaminosulfonyl-                                              phenyl)phenyl                                                               404 1 C(O) 4-(2-ethylaminosulfonyl-                                               phenyl)-2-pyridyl                                                           405 1 C(O) 2-aminosulfonyl-4-                                                     cyclohexylphenyl                                                            406 1 C(O) 3-aminosulfonyl-4-t-butyl-2-                                           pyridyl                                                                     407 1 C(O) 2-(5-indazol-5-yl)furanyl                                           408 1 C(O) 2-(5-indazol-6-yl)thienyl                                           409 1 C(O) 4-(2-tetrazolylphenyl)phenyl                                        410 1 C(O)NH 4-(2-                                                                aminosulfonylphenyl)phenyl                                                  411 1 C(O)NH 4-(2-aminosulfonylphenyl)-2-                                         pyridyl                                                                     412 1 C(O)NH 4-(2-methylaminosulfonyl-                                            phenyl)phenyl                                                               413 1 C(O)NH 4-(2-ethylaminosulfonyl-                                             phenyl)-2-pyridyl                                                           414 1 C(O)NH 2-aminosulfonyl-4-                                                   cyclohexylphenyl                                                            415 1 C(O)NH 3-aminosulfonyl-4-t-butyl-2-                                         pyridyl                                                                     416 1 C(O)NH 2-(5-indazol-5-yl)furanyl                                         417 1 C(O)NH 2-(5-indazol-6-yl)thienyl                                         418 1 C(O)NH 4-(2-tetrazolylphenyl)phenyl                                      419 1 NHC(O) 4-(2-                                                                aminosulfonylphenyl)phenyl                                                  420 1 NHC(O) 4-(2-aminosulfonylphenyl)-2-                                         pyridyl                                                                     421 1 NHC(O) 4-(2-methylaminosulfonyl-                                            phenyl)phenyl                                                               422 1 NHC(O) 4-(2-ethylaminosulfonyl-                                             phenyl)-2-pyridyl                                                           423 1 NHC(O) 2-aminosulfonyl-4-                                                   cyclohexylphenyl                                                            424 1 NHC(O) 3-aminosulfonyl-4-t-butyl-2-                                         pyridyl                                                                     425 1 NHC(O) 2-(5-indazol-5-yl)furanyl                                         426 1 NHC(O) 2-(5-indazol-6-yl)thienyl                                         427 1 NHC(O) 4-(2-tetrazolylphenyl)phenyl                                      428 1 SO.sub.2 NH 4-(2-                                                           aminosulfonylphenyl)phenyl                                                  429 1 SO.sub.2 NH 4-(2-aminosulfonylphenyl)-2-                                    pyridyl                                                                     430 1 SO.sub.2 NH 4-(2-methylaminosulfonyl-                                       phenyl)phenyl                                                               431 1 SO.sub.2 NH 4-(2-ethylaminosulfonyl-                                        phenyl)-2-pyridyl                                                           432 1 SO.sub.2 NH 2-aminosulfonyl-4-                                              cyclohexylphenyl                                                            433 1 SO.sub.2 NH 3-aminosulfonyl-4-t-butyl-2-                                    pyridyl                                                                     434 1 SO.sub.2 NH 2-(5-indazol-5-yl)furanyl                                    435 1 SO.sub.2 NH 2-(5-indazol-6-yl)thienyl                                    436 1 SO.sub.2 NH 4-(2-tetrazolylphenyl)phenyl                                 437 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-                                        aminosulfonylphenyl)phenyl                                                  438 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-aminosulfonylphenyl)-2-                                            pyridyl                                          439 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-methylaminosulfonyl-                    phenyl)phenyl                                                               440 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-ethylaminosulfonyl-                     phenyl)-2-pyridyl                                                           441 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-aminosulfonyl-4-                           cyclohexylphenyl                                                            442 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 3-aminosulfonyl-4-t-butyl-2-                                            pyridyl                                          443 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-(5-indazol-5-1)furanyl                  444 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-(5-indazol-6-yl)thienyl                 445 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-tetrazolylphenyl)phenyl                                         446 0 CH(CH.sub.2 - 4-(2-                             tetrazolyl)C(O)NH aminosulfonylphenyl)phenyl                                 447 0 CH(CH.sub.2 - 4-(2-aminosulfonylphenyl)-2-                                 tetrazolyl)C(O)NH pyridyl                                                    448 0 CH(CH.sub.2 - 4-(2-methylaminosulfonyl-                                    tetrazolyl)C(O)NH phenyl)phenyl                                              449 0 CH(CH.sub.2 - 4-(2-ethylaminosulfonyl-                                     tetrazolyl)C(O)NH phenyl)-2-pyridyl                                          450 0 CH(CH.sub.2 - 2-aminosulfonyl-4-                                           tetrazolyl)C(O)NH cyclohexylphenyl                                           451 0 CH(CH.sub.2 - 3-aminosulfonyl-4-t-butyl-2-                                 tetrazolyl)C(O)NH pyridyl                                                    452 0 CH(CH.sub.2 - 2-(5-indazol-5-yl)furanyl                                    tetrazolyl)C(O)NH                                                            453 0 CH(CH.sub.2 - 2-(5-indazol-6-yl)thienyl                                    tetrazolyl)C(O)NH                                                            454 0 CH(CH.sub.2 - 4-(2-tetrazolylphenyl)phenyl                                 tetrazolyl)C(O)NH                                                          ______________________________________                                    

                  TABLE 11                                                         ______________________________________                                           #STR43##                                                                       Ex     n     Z             A--B                                              ______________________________________                                         501  1     C(O)            4-(2-aminosulfonylphenyl)-2-                             pyridyl                                                                     502 1 C(O) 4-(2-methylaminosulfonyl-                                              phenyl)phenyl                                                               503 1 C(O) 4-(2-ethylaminosulfonyl-                                               phenyl)-2-pyridyl                                                           504 1 C(O) 2-aminosulfonyl-4-                                                     cyclohexylphenyl                                                            505 1 C(O) 3-aminosulfonyl-4-t-butyl-2-                                           pyridyl                                                                     506 1 C(O) 2-(5-indazol-5-yl)furanyl                                           507 1 C(O) 2-(5-indazol-6-yl)thienyl                                           508 1 C(O) 4-(2-tetrazolylphenyl)phenyl                                        509 1 C(O)NH 4-(2-aminosulfonylphenyl)-2-                                         pyridyl                                                                     510 1 C(O)NH 4-(2-methylaminosulfonyl-                                            phenyl)phenyl                                                               511 1 C(O)NH 4-(2-ethylaminosulfonyl-                                             phenyl)-2-pyridyl                                                           512 1 C(O)NH 2-aminosulfonyl-4-                                                   cyclohexylphenyl                                                            513 1 C(O)NH 3-aminosulfonyl-4-t-butyl-2-                                         pyridyl                                                                     514 1 C(O)NH 2-(5-indazol-5-yl)furanyl                                         515 1 C(O)NH 2-(5-indazol-6-yl)thienyl                                         516 1 C(O)NH 4-(2-tetrazolylphenyl)phenyl                                      517 1 NHC(O) 4-(2-                                                                aminosulfonylphenyl)phenyl                                                  518 1 NHC(O) 4-(2-aminosulfonylphenyl)-2-                                         pyridyl                                                                     519 1 NHC(O) 4-(2-methylaminosulfonyl-                                            phenyl)phenyl                                                               520 1 NHC(O) 4-(2-ethylaminosulfonyl-                                             phenyl)-2-pyridyl                                                           521 1 NHC(O) 2-aminosulfonyl-4-                                                   cyclohexylphenyl                                                            522 1 NHC(O) 3-aminosulfonyl-4-t-butyl-2-                                         pyridyl                                                                     523 1 NHC(O) 2-(5-indazol-5-yl)furanyl                                         524 1 NHC(O) 2-(5-indazol-6-yl)thienyl                                         525 1 NHC(O) 4-(2-tetrazolylphenyl)phenyl                                      526 1 SO.sub.2 NH 4-(2-aminosulfonyl-                                             phenyl)phenyl                                                               527 1 SO.sub.2 NH 4-(2-aminosulfonylphenyl)-2-                                    pyridyl                                                                     528 1 SO.sub.2 NH 4-(2-methylaminosulfonyl-                                       phenyl)phenyl                                                               529 1 SO.sub.2 NH 4-(2-ethylaminosulfonyl-                                        phenyl)-2-pyridyl                                                           530 1 SO.sub.2 NH 2-aminosulfonyl-4-                                              cyclohexylphenyl                                                            531 1 SO.sub.2 NH 3-aminosulfonyl-4-t-butyl-2-                                    pyridyl                                                                     532 1 SO.sub.2 NH 2-(5-indazol-5-yl)furanyl                                    533 1 SO.sub.2 NH 2-(5-indazol-6-yl)thienyl                                    534 1 SO.sub.2 NH 4-(2-tetrazolylphenyl)phenyl                                 535 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-                                        aminosulfonylphenyl)phenyl                                                  536 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-aminosulfonylphenyl)-2-                                           pyridyl                                           537 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-methylaminosulfonyl-                    phenyl)phenyl                                                               538 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-ethylaminosulfonyl-                     phenyl)-2-pyridyl                                                           539 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-aminosulfonyl-4-                           cyclohexylphenyl                                                            540 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 3-aminosulfonyl-4-t-butyl-2-                                           pyridyl                                           541 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-(5-indazol-5-yl)furanyl                 542 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-(5-indazol-6-yl)thienyl                 543 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-tetrazolylphenyl)phenyl                                        544 0 CH(CH.sub.2 - 4-(2-                              tetrazolyl)C(O)NH aminosulfonylphenyl)phenyl                                 545 0 CH(CH.sub.2 - 4-(2-aminosulfonylphenyl)-2-                                 tetrazolyl)C(O)NH pyridyl                                                    546 0 CH(CH.sub.2 - 4-(2-methylaminosulfonyl-                                    tetrazolyl)C(O)NH phenyl)phenyl                                              547 0 CH(CH.sub.2 - 4-(2-ethylaminosulfonyl-                                     tetrazolyl)C(O)NH phenyl)-2-pyridyl                                          548 0 CH(CH.sub.2 - 2-aminosulfonyl-4-                                           tetrazolyl)C(O)NH cyclohexylphenyl                                           549 0 CH(CH.sub.2 - 3-aminosulfonyl-4-t-butyl-2-                                 tetrazolyl)C(O)NH pyridyl                                                    550 0 CH(CH.sub.2 - 2-(5-indazol-5-yl)furanyl                                    tetrazolyl)C(O)NH                                                            551 0 CH(CH.sub.2 - 2-(5-indazol-6-yl)thienyl                                    tetrazolyl)C(O)NH                                                            552 0 CH(CH.sub.2 - 4-(2-tetrazolylphenyl)phenyl                                 tetrazolyl)C(O)NH                                                          ______________________________________                                    

                  TABLE 12                                                         ______________________________________                                           #STR44##                                                                       Ex     n     Z             A--B                                              ______________________________________                                         601  1     C(O)            4-(2-                                                    aminosulfonylphenyl)phenyl                                                  602 1 C(O) 4-(2-aminosulfonylphenyl)-2-                                           pyridyl                                                                     603 1 C(O) 4-(2-methylaminosulfonyl-                                              phenyl)phenyl                                                               604 1 C(O) 4-(2-ethylaminosulfonyl-                                               phenyl)-2-pyridyl                                                           605 1 C(O) 2-aminosulfonyl-4-                                                     cyclohexylphenyl                                                            606 1 C(O) 3-aminosulfonyl-4-t-butyl-2-                                           pyridyl                                                                     607 1 C(O) 2-(5-indazol-5-yl)furanyl                                           608 1 C(O) 2-(5-indazol-6-yl)thienyl                                           609 1 C(O) 4-(2-tetrazolylphenyl)phenyl                                        610 1 C(O)NH 4-(2-                                                                aminosulfonylphenyl)phenyl                                                  611 1 C(O)NH 4-(2-aminosulfonylphenyl-2-                                          pyridyl                                                                     612 1 C(O)NH 4-(2-methylaminosulfonyl-                                            phenyl)phenyl                                                               613 1 C(O)NH 4-(2-ethylaminosulfonyl-                                             phenyl)-2-pyridyl                                                           614 1 C(O)NH 2-aminosulfonyl-4-                                                   cyclohexylphenyl                                                            615 1 C(O)NH 3-aminosulfonyl-4-t-butyl-2-                                         pyridyl                                                                     616 1 C(O)NH 2-(5-indazol-5-yl)furanyl                                         617 1 C(O)NH 2-(5-indazol-6-yl)thienyl                                         618 1 C(O)NH 4-(2-tetrazolylphenyl)phenyl                                      619 1 NHC(O) 4-(2-                                                                aminosulfonylphenyl)phenyl                                                  620 1 NHC(O) 4-(2-aminosulfonylphenyl)-2-                                         pyridyl                                                                     621 1 NHC(O) 4-(2-methylaminosulfonyl-                                            phenyl)phenyl                                                               622 1 NHC(O) 4-(2-ethylaminosulfonyl-                                             phenyl)-2-pyridyl                                                           623 1 NHC(O) 2-aminosulfonyl-4-                                                   cyclohexylphenyl                                                            624 1 NHC(O) 3-aminosulfonyl-4-t-butyl-2-                                         pyridyl                                                                     625 1 NHC(O) 2-(5-indazol-5-yl)furanyl                                         626 1 NHC(O) 2-(5-indazol-6-yl)thienyl                                         627 1 NHC(O) 4-(2-tetrazolylphenyl)phenyl                                      628 1 SO.sub.2 NH 4-(2-                                                           aminosulfonylphenyl)phenyl                                                  629 1 SO.sub.2 NH 4-(2-aminosulfonylphenyl)-2-                                    pyridyl                                                                     630 1 SO.sub.2 NH 4-(2-methylaminosulfonyl-                                       phenyl)phenyl                                                               631 1 SO.sub.2 NH 4-(2-ethylaminosulfonyl-                                        phenyl)-2-pyridyl                                                           632 1 SO.sub.2 NH 2-aminosulfonyl-4-                                              cyclohexylphenyl                                                            633 1 SO.sub.2 NH 3-aminosulfonyl-4-t-butyl-2-                                    pyridyl                                                                     634 1 SO.sub.2 NH 2-(5-indazol-5-yl)furanyl                                    635 1 SO.sub.2 NH 2-(5-indazol-6-yl)thienyl                                    636 1 SO.sub.2 NH 4-(2-tetrazolylphenyl)phenyl                                 637 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-                                        aminosulfonylphenyl)phenyl                                                  638 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-aminosulfonylphenyl)-2-                                           pyridyl                                           639 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-methylaminosulfonyl-                    phenyl)phenyl                                                               640 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-ethylaminosulfonyl-                     phenyl)-2-pyridyl                                                           641 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-aminosulfonyl-4-                           cyclohexylphenyl                                                            642 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 3-aminosulfonyl-4-t-butyl-2-                                           pyridyl                                           643 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-(5-indazol-5-yl)furanyl                 644 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-(5-indazol-6-yl)thienyl                 645 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-tetrazolylphenyl)phenyl                                        646 0 CH(CH.sub.2 - 4-(2-                              tetrazolyl)C(O)NH aminosulfonylphenyl)phenyl                                 647 0 CH(CH.sub.2 - 4-(2-aminosulfonylphenyl)-2-                                 tetrazolyl)C(O)NH pyridyl                                                    648 0 CH(CH.sub.2 - 4-(2-methylaminosulfonyl-                                    tetrazolyl)C(O)NH phenyl)phenyl                                              649 0 CH(CH.sub.2 - 4-(2-ethylaminosulfonyl-                                     tetrazolyl)C(O)NH phenyl)-2-pyridyl                                          650 0 CH(CH.sub.2 - 2-aminosulfonyl-4-                                           tetrazolyl)C(O)NH cyclohexylphenyl                                           651 0 CH(CH.sub.2 - 3-aminosulfonyl-4-t-butyl-2-                                 tetrazolyl)C(O)NH pyridyl                                                    652 0 CH(CH.sub.2 - 2-(5-indazol-5-yl)furanyl                                    tetrazolyl)C(O)NH                                                            653 0 CH(CH.sub.2 - 2-(5-indazol-6-yl)thienyl                                    tetrazolyl)C(O)NH                                                            654 0 CH(CH.sub.2 - 4-(2-tetrazolylphenyl)phenyl                                 tetrazolyl)C(O)NH                                                          ______________________________________                                    

                  TABLE 13                                                         ______________________________________                                           #STR45##                                                                       Ex     n      Z             A--B                                             ______________________________________                                         701  1      C(O)            4-(2-                                                   aminosulfonylphenyl)phenyl                                                  702 1 C(O) 4-(2-aminosulfonylphenyl)-2-                                           pyridyl                                                                     703 1 C(O) 4-(2-methylaminosulfonyl-                                              phenyl)phenyl                                                               704 1 C(O) 4-(2-ethylaminosulfonyl-                                               phenyl)-2-pyridyl                                                           705 1 C(O) 2-aminosulfonyl-4-                                                     cyclohexylphenyl                                                            706 1 C(O) 3-aminosulfonyl-4-t-butyl-2-                                           pyridyl                                                                     707 1 C(O) 2-(5-indazol-5-yl)furanyl                                           708 1 C(O) 2-(5-indazol-6-yl)thienyl                                           709 1 C(O) 4-(2-tetrazolylphenyl)phenyl                                        710 1 C(O)NH 4-(2-methylaminosulfonyl-                                            phenyl)phenyl                                                               711 1 C(O)NH 4-(2-ethylaminosulfonyl-                                             phenyl)-2-pyridyl                                                           712 1 C(O)NH 2-aminosulfonyl-4-                                                   cyclohexylphenyl                                                            713 1 C(O)NH 3-aminosulfonyl-4-t-butyl-2-                                         pyridyl                                                                     714 1 C(O)NH 2-(5-indazol-5-yl)furanyl                                         715 1 C(O)NH 2-(5-indazol-6-yl)thienyl                                         716 1 C(O)NH 4-(2-tetrazolylphenyl)phenyl                                      717 1 NHC(O) 4-(2-                                                                aminosulfonylphenyl)phenyl                                                  718 1 NHC(O) 4-(2-aminosulfonylphenyl)-2-                                         pyridyl                                                                     719 1 NHC(O) 4-(2-methylaminosulfonyl-                                            phenyl)phenyl                                                               720 1 NHC(O) 4-(2-ethylaminosulfonyl-                                             phenyl)-2-pyridyl                                                           721 1 NHC(O) 2-aminosulfonyl-4-                                                   cyclohexylphenyl                                                            722 1 NHC(O) 3-aminosulfonyl-4-t-butyl-2-                                         pyridyl                                                                     723 1 NHC(O) 2-(5-indazol-5-yl)furanyl                                         724 1 NHC(O) 2-(5-indazol-6-yl)thienyl                                         725 1 NHC(O) 4-(2-tetrazolylphenyl)phenyl                                      726 1 SO.sub.2 NH 4-(2-                                                           aminosulfonylphenyl)phenyl                                                  727 1 SO.sub.2 NH 4-(2-aminosulfonylphenyl)-2-                                    pyridyl                                                                     728 1 SO.sub.2 NH 4-(2-methylaminosulfonyl-                                       phenyl)phenyl                                                               729 1 SO.sub.2 NH 4-(2-ethylaminosulfonyl-                                        phenyl)-2-pyridyl                                                           730 1 SO.sub.2 NH 2-aminosulfonyl-4-                                              cyclohexylphenyl                                                            731 1 SO.sub.2 NH 3-aminosulfonyl-4-t-butyl-2-                                    pyridyl                                                                     732 1 SO.sub.2 NH 2-(5-indazol-5-yl)furanyl                                    733 1 SO.sub.2 NH 2-(5-indazol-6-yl)thienyl                                    734 1 SO.sub.2 NH 4-(2-tetrazolylphenyl)phenyl                                 735 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-                                        aminosulfonylphenyl)phenyl                                                  736 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-aminosulfonylphenyl)-2-                                            pyridyl                                          737 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-methylaminosulfonyl-                    phenyl)phenyl                                                               738 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-ethylaminosulfonyl-                     phenyl)-2-pyridyl                                                           739 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-aminosulfonyl-4-                           cyclohexylphenyl                                                            740 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 3-aminosulfonyl-4-t-butyl-2-                                            pyridyl                                          741 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-(5-indazol-5-yl)furanyl                 742 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-(5-indazol-6-yl)thienyl                 743 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-tetrazolylphenyl)phenyl                                         744 0 CH(CH.sub.2 - 4-(2-                             tetrazolyl)C(O)NH aminosulfonylphenyl)phenyl                                 745 0 CH(CH.sub.2 - 4-(2-aminosulfonylphenyl)-2-                                 tetrazolyl)C(O)NH pyridyl                                                    746 0 CH(CH.sub.2 - 4-(2-methylaminosulfonyl-                                    tetrazolyl)C(O)NH phenyl)phenyl                                              747 0 CH(CH.sub.2 - 4-(2-ethylaminosulfonyl-                                     tetrazolyl)C(O)NH phenyl)-2-pyridyl                                          748 0 CH(CH.sub.2 - 2-aminosulfonyl-4-                                           tetrazolyl)C(O)NH cyclohexylphenyl                                           749 0 CH(CH.sub.2 - 3-aminosulfonyl-4-t-butyl-2-                                 tetrazolyl)C(O)NH pyridyl                                                    750 0 CH(CH.sub.2 - 2-(5-indazol-5-yl)furanyl                                    tetrazolyl)C(O)NH                                                            751 0 CH(CH.sub.2 - 2-(5-indazol-6-yl)thienyl                                    tetrazolyl)C(O)NH                                                            752 0 CH(CH.sub.2 - 4-(2-tetrazolylphenyl)phenyl                                 tetrazolyl)C(O)NH                                                          ______________________________________                                    

                  TABLE 14                                                         ______________________________________                                           #STR46##                                                                       Ex     n     Z             A--B                                              ______________________________________                                         801  1     C(O)            4-(2-                                                    aminosulfonylphenyl)phenyl                                                  802 1 C(O) 4-(2-aminosulfonylphenyl)-2-                                           pyridyl                                                                     803 1 C(O) 4-(2-methylaminosulfonyl-                                              phenyl)phenyl                                                               804 1 C(O) 4-(2-ethylaminosulfonyl-                                               phenyl)-2-pyridyl                                                           805 1 C(O) 2-aminosulfonyl-4-                                                     cyclohexylphenyl                                                            806 1 C(O) 3-aminosulfonyl-4-t-butyl-2-                                           pyridyl                                                                     807 1 C(O) 2-(5-indazol-5-yl)furanyl                                           808 1 C(O) 2-(5-indazol-6-yl)thienyl                                           809 1 C(O) 4-(2-tetrazolylphenyl)phenyl                                        810 1 C(O)NH 4-(2-                                                                aminosulfonylphenyl)phenyl                                                  811 1 C(O)NH 4-(2-aminosulfonylphenyl)-2                                          pyridyl                                                                     812 1 C(O)NH 4-(2-methylaminosulfonyl-                                            phenyl)phenyl                                                               813 1 C(O)NH 4-(2-ethylaminosulfonyl-                                             phenyl-2-pyridyl                                                            814 1 C(O)NH 2-aminosulfonyl-4-                                                   cyclohexylphenyl                                                            815 1 C(O)NH 3-aminosulfonyl-4-t-butyl-2-                                         pyridyl                                                                     816 1 C(O)NH 2-(5-indazol-5-yl)furanyl                                         817 1 C(O)NH 2-(5-indazol-6-yl)thienyl                                         818 1 C(O)NH 4-(2-tetrazolylphenyl)phenyl                                      819 1 NHC(O) 4-(2-                                                                aminosulfonylphenyl)phenyl                                                  820 1 NHC(O) 4-(2-aminosulfonylphenyl)-2-                                         pyridyl                                                                     821 1 NHC(O) 4-(2-methylaminosulfonyl-                                            phenyl)phenyl                                                               822 1 NHC(O) 4-(2-ethylaminosulfonyl-                                             phenyl)-2-pyridyl                                                           823 1 NHC(O) 2-aminosulfonyl-4-                                                   cyclohexylphenyl                                                            824 1 NHC(O) 3-aminosulfonyl-4-t-butyl-2-                                         pyridyl                                                                     825 1 NHC(O) 2-(5-indazol-5-yl)furanyl                                         826 1 NHC(O) 2-(5-indazol-6-yl)thienyl                                         827 1 NHC(O) 4-(2-tetrazolylphenyl)phenyl                                      828 1 SO.sub.2 NH 4-(2-                                                           aminosulfonylphenyl)phenyl                                                  829 1 SO.sub.2 NH 4-(2-aminosulfonylphenyl)-2-                                    pyridyl                                                                     830 1 SO.sub.2 NH 4-(2-methylaminosulfonyl-                                       phenyl)phenyl                                                               831 1 SO.sub.2 NH 4-(2-ethylaminosulfonyl-                                        phenyl)-2-pyridyl                                                           832 1 SO.sub.2 NH 2-aminosulfonyl-4-                                              cyclohexylphenyl                                                            833 1 SO.sub.2 NH 3-aminosulfonyl-4-t-butyl-2-                                    pyridyl                                                                     834 1 SO.sub.2 NH 2-(5-indazol-5-yl)furanyl                                    835 1 SO.sub.2 NH 2-(5-indazol-6-yl)thienyl                                    836 1 SO.sub.2 NH 4-(2-tetrazolylphenyl)phenyl                                 837 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-                                        aminosulfonylphenyl)phenyl                                                  838 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-aminosulfonylphenyl)-2-                                           pyridyl                                           839 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-methylaminosulfonyl-                    phenyl)phenyl                                                               840 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-ethylaminosulfonyl-                     phenyl)-2-pyridyl                                                           841 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-aminosulfonyl-4-                           cyclohexylphenyl                                                            842 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 3-aminosulfonyl-4-t-butyl-2-                                           pyridyl                                           843 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-(5-indazol-5-yl)furanyl                 844 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-(5-indazol-6-yl)thienyl                 845 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-tetrazolylphenyl)phenyl                                        846 0 CH(CH.sub.2 - 4-(2-                              tetrazolyl)C(O)NH aminosulfonylphenyl)phenyl                                 847 0 CH(CH.sub.2 - 4-(2-aminosulfonylphenyl)-2-                                 tetrazolyl)C(O)NH pyridyl                                                    848 0 CH(CH.sub.2 - 4-(2-methylaminosulfonyl-                                    tetrazolyl)C(O)NH phenyl)phenyl                                              849 0 CH(CH.sub.2 - 4-(2-ethylaminosulfonyl-                                     tetrazolyl)C(O)NH phenyl)-2-pyridyl                                          850 0 CH(CH.sub.2 - 2-aminosulfonyl-4-                                           tetrazolyl)C(O)NH cyclohexylphenyl                                           851 0 CH(CH.sub.2 - 3-aminosulfonyl-4-t-butyl-2-                                 tetrazolyl)C(O)NH pyridyl                                                    852 0 CH(CH.sub.2 - 2-(5-indazol-5-yl)furanyl                                    tetrazolyl)C(O)NH                                                            853 0 CH(CH.sub.2 - 2-(5-indazol-6-yl)thienyl                                    tetrazolyl)C(O)NH                                                            854 0 CH(CH.sub.2 - 4-(2-tetrazolylphenyl)phenyl                                 tetrazolyl)C(O)NH                                                          ______________________________________                                    

                  TABLE 15                                                         ______________________________________                                           #STR47##                                                                       Ex     n      Z             A--B                                             ______________________________________                                         901  1      C(O)            4-(2-                                                   aminosulfonylphenyl)phenyl                                                  902 1 C(O) 4-(2-aminosulfonylphenyl)-2-                                           pyridyl                                                                     903 1 C(O) 4-(2-methylaminosulfonyl-                                              phenyl)phenyl                                                               904 1 C(O) 4-(2-ethylaminosulfonyl-                                               phenyl)-2-pyridyl                                                           905 1 C(O) 2-aminosulfonyl-4-                                                     cyclohexylphenyl                                                            906 1 C(O) 3-aminosulfonyl-4-t-butyl-2-                                           pyridyl                                                                     907 1 C(O) 2-(5-indazol-5-yl)furanyl                                           908 1 C(O) 2-(5-indazol-6-yl)thienyl                                           909 1 C(O) 4-(2-tetrazolylphenyl)phenyl                                        910 1 C(O)NH 4-(2-                                                                aminosulfonylphenyl)phenyl                                                  911 1 C(O)NH 4-(2-aminosulfonylphenyl)-2-                                         pyridyl                                                                     912 1 C(O)NH 4-(2-methylaminosulfonyl-                                            phenyl)phenyl                                                               913 1 C(O)NH 4-(2-ethylaminosulfonyl-                                             phenyl)-2-pyridyl                                                           914 1 C(O)NH 2-aminosulfonyl-4-                                                   cyclohexylphenyl                                                            915 1 C(O)NH 3-aminosulfonyl-4-t-butyl-2-                                         pyridyl                                                                     916 1 C(O)NH 2-(5-indazol-5-yl)furanyl                                         917 1 C(O)NH 2-(5-indazol-6-yl)thienyl                                         918 1 C(O)NH 4-(2-tetrazolylphenyl)phenyl                                      919 1 NHC(O) 4-(2-                                                                aminosulfonylphenyl)phenyl                                                  920 1 NHC(O) 4-(2-aminosulfonylphenyl)-2-                                         pyridyl                                                                     921 1 NHC(O) 4-(2-methylaminosulfonyl-                                            phenyl)phenyl                                                               922 1 NHC(O) 4-(2-ethylaminosulfonyl-                                             phenyl)-2-pyridyl                                                           923 1 NHC(O) 2-aminosulfonyl-4-                                                   cyclohexylphenyl                                                            924 1 NHC(O) 3-aminosulfonyl-4-t-butyl-2-                                         pyridyl                                                                     925 1 NHC(O) 2-(5-indazol-5-yl)furanyl                                         926 1 NHC(O) 2-(5-indazol-6-yl)thienyl                                         927 1 NHC(O) 4-(2-tetrazolylphenyl)phenyl                                      928 1 SO.sub.2 NH 4-(2-                                                           aminosulfonylphenyl)phenyl                                                  929 1 SO.sub.2 NH 4-(2-aminosulfonylphenyl)-2-                                    pyridyl                                                                     930 1 SO.sub.2 NH 4-(2-methylaminosulfonyl-                                       phenyl)phenyl                                                               931 1 SO.sub.2 NH 4-(2-ethylaminosulfonyl-                                        phenyl)-2-pyridyl                                                           932 1 SO.sub.2 NH 2-aminosulfonyl-4-                                              cyclohexylphenyl                                                            933 1 SO.sub.2 NH 3-aminosulfonyl-4-t-butyl-2-                                    pyridyl                                                                     934 1 SO.sub.2 NH 2-(5-indazol-5-yl)furanyl                                    935 1 SO.sub.2 NH 2-(5-indazol-6-yl)thienyl                                    936 1 SO.sub.2 NH 4-(2-tetrazolylphenyl)phenyl                                 937 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-                                        aminosulfonylphenyl)phenyl                                                  938 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-aminosulfonylphenyl)-2-                                            pyridyl                                          939 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-methylaminosulfonyl-                    phenyl)phenyl                                                               940 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-ethylaminosulfonyl-                     phenyl)-2-pyridyl                                                           941 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-aminosulfonyl-4-                           cyclohexylphenyl                                                            942 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 3-aminosulfonyl-4-t-butyl-2-                                            pyridyl                                          943 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-(5-indazol-5-yl)furanyl                 944 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-(5-indazol-6-yl)thienyl                 945 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-tetrazolylphenyl)phenyl                                         946 0 CH(CH.sub.2 - 4-(2-                             tetrazolyl)C(O)NH aminosulfonylphenyl)phenyl                                 947 0 CH(CH.sub.2 - 4-(2-aminosulfonylphenyl)-2-                                 tetrazolyl)C(O)NH pyridyl                                                    948 0 CH(CH.sub.2 - 4-(2-methylaminosulfonyl-                                    tetrazolyl)C(O)NH phenyl)phenyl                                              949 0 CH(CH.sub.2 - 4-(2-ethylaminosulfonyl-                                     tetrazolyl)C(O)NH phenyl)-2-pyridyl                                          950 0 CH(CH.sub.2 - 2-aminosulfonyl-4-                                           tetrazolyl)C(O)NH cyclohexylphenyl                                           951 0 CH(CH.sub.2 - 3-aminosulfonyl-4-t-butyl-2-                                 tetrazolyl)C(O)NH pyridyl                                                    952 0 CH(CH.sub.2 - 2-(5-indazol-5-yl)furanyl                                    tetrazolyl)C(O)NH                                                            953 0 CH(CH.sub.2 - 2-(5-indazol-6-yl)thienyl                                    tetrazolyl)C(O)NH                                                            954 0 CH(CH.sub.2 - 4-(2-tetrazolylphenyl)phenyl                                 tetrazolyl)C(O)NH                                                          ______________________________________                                    

                  TABLE 16                                                         ______________________________________                                           #STR48##                                                                       Ex     n     Z              A-B                                              ______________________________________                                         1001 1     C(O)             4-(2-                                                   aminosulfonylphenyl)phenyl                                                  1002 1 C(O) 4-(2-aminosulfonylphenyl)-2-                                          pyridyl                                                                     1003 1 C(O) 4-(2-methylaminosulfonyl-                                             phenyl) phenyl                                                              1004 1 C(O) 4-(2-ethylaminosulfonyl-                                              phenyl)-2-pyridyl                                                           1005 1 C(O) 2-aminosulfonyl-4-                                                    cyclohexylphenyl                                                            1006 1 C(O) 3-aminosulfonyl-4-t-butyl-2-                                          pyridyl                                                                     1007  C(O) 2-(5-indazol-5-yl)furanyl                                           1008 1 C(O) 2-(5-indazol-6-yl)thienyl                                          1009 1 C(O) 4-(2-tetrazolylphenyl)phenyl                                       1010 1 C(O)NH 4-(2-                                                               aminosulfonylphenyl)phenyl                                                  1011 1 C(O)NH 4-(2-aminosulfonylphenyl)-2-                                        pyridyl                                                                     1012 1 C(O)NH 4-(2-methylaminosulfonyl-                                           phenyl)phenyl                                                               1013 1 C(O)NH 4-(2-ethylaminosulfonyl-                                            phenyl)-2-pyridyl                                                           1014 1 C(O)NH 2-aminosulfonyl-4-                                                  cyclohexylphenyl                                                            1015 1 C(O)NH 3-aminosulfonyl-4-t-butyl-2-                                        pyridyl                                                                     1016 1 C(O)NH 2-(5-indazol-5-yl)furanyl                                        1017 1 C(O)NH 2-(5-indazol-6-yl)thienyl                                        1018 1 C(O)NH 4-(2-tetrazolylphenyl)phenyl                                     1019 1 NHC(O) 4-(2-                                                               aminosulfonylphenyl)phenyl                                                  1020 1 NHC(O) 4-(2-aminosulfonylphenyl)-2-                                        pyridyl                                                                     1021 1 NHC(O) 4-(2-methylaminosulfonyl-                                           phenyl)phenyl                                                               1022 1 NHC(O) 4-(2-ethylaminosulfonyl-                                            phenyl)-2-pyridyl                                                           1023 1 NHC(O) 2-aminosulfonyl-4-                                                  cyclohexylphenyl                                                            1024 1 NHC(O) 3-aminosulfonyl-4-t-butyl-2-                                        pyridyl                                                                     1025 1 NHC(O) 2-(5-indazol-5-yl)furanyl                                        1026 1 NHC(O) 2-(5-indazol-6-yl)thienyl                                        1027 1 NHC(O) 4-(2-tetrazolylphenyl)phenyl                                     1028 1 SO.sub.2 NH 4-(2-                                                          aminosulfonylphenyl)phenyl                                                  1029 1 SO.sub.2 NH 4-(2-aminosulfonylphenyl)-2-                                   pyridyl                                                                     1030 1 SO.sub.2 NH 4-(2-methylaminosulfonyl-                                      phenyl)phenyl                                                               1031 1 SO.sub.2 NH 4-(2-ethylaminosulfonyl-                                       phenyl)-2-pyridyl                                                           1032 1 SO.sub.2 NH 2-aminosulfonyl-4-                                             cyclohexylphenyl                                                            1033 1 SO.sub.2 NH 3-aminosulfonyl-4-t-butyl-2-                                   pyridyl                                                                     1034 1 SO.sub.2 NH 2-(5-indazol-5-yl)furanyl                                   1035 1 SO.sub.2 NH 2-(5-indazol-6-yl)thienyl                                   1036 1 SO.sub.2 NH 4-(2-tetrazolylphenyl)phenyl                                1037 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-                                       aminosulfonylphenyl)phenyl                                                  1038 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-aminosulfonylphenyl)-2-                                           pyridyl                                          1039 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-methylaminosulfonyl-                                              phenyl)phenyl                                    1040 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-ethylaminosulfonyl-                    phenyl)-2-pyridyl                                                           1041 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-aminosulfonyl-4-                          cyclohexylphenyl                                                            1042 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 3-aminosulfonyl-4-t-butyl-2-                                           pyridyl                                          1043 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-(5-indazol-5-yl)furanyl                                           1044 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH                                         2-(5-indazol-6-yl)thienyl                            1045 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-tetrazolylphenyl)phenyl                                        1046 0 CH(CH.sub.2 - 4-(2-                            tetrazolyl)C(O)NH aminosulfonylphenyl)phenyl                                 1047 0 CH(CH.sub.2 - 4-(2-aminosulfonylphenyl)-2-                                tetrazolyl)C(O)NH pyridyl                                                    1048 0 CH(CH.sub.2 - 4-(2-methylaminosulfonyl-                                   tetrazolyl)C(O)NH phenyl)phenyl                                              1049 0 CH(CH.sub.2 - 4-(2-ethylaminosulfonyl-                                    tetrazolyl)C(O)NH phenyl)-2-pyridyl                                          1050 0 CH(CH.sub.2 - 2-aminosulfonyl-4-                                          tetrazolyl)C(O)NH cyclohexylphenyl                                           1051 0 CH(CH.sub.2 - 3-aminosulfonyl-4-t-butyl-2-                                tetrazolyl)C(O)NH pyridyl                                                    1052 0 CH(CH.sub.2 - 2-(5-indazol-5-yl)furanyl                                   tetrazolyl)C(O)NH                                                            1053 0 CH(CH.sub.2 - 2-(5-indazol-6-yl)thienyl                                   tetrazolyl)C(O)NH                                                            1054 0 CH(CH.sub.2 - 4-(2-tetrazolylphenyl)phenyl                                tetrazolyl)C(O)NH                                                          ______________________________________                                    

                  TABLE 17                                                         ______________________________________                                           #STR49##                                                                       Ex     n      Z      R.sup.1  A-B                                            ______________________________________                                         1101 1      C(O)     H        3-acetyl-4-benzylpiperidine                        1102 1 C(O) H 4-(4-fluorobenzyl)piperidine                                     1103 1 C(O) H 4-(2,3-difluorobenzyl)                                               piperidine                                                                 1104 1 C(O) H 4-(2-chloro-4-fluorobenzyl)                                          piperidine                                                                 1105 1 C(O) CH.sub.2 CH.sub.2 OH 3-acetyl-4-benzylpiperidine                   1106 1 C(O) CH.sub.2 CH.sub.2 OH 4-(3-fluorobenzyl)piperidine                  1107 1 C(O) CH.sub.2 CH.sub.2 OH 4-(4-fluorobenzyl)piperidine                  1108 1 C(O) CH.sub.2 CH.sub.2 OH 4-(2,3-difluorobenzyl)                            piperidine                                                                 1109 1 C(O) CH.sub.2 CH.sub.2 OH 4-(2-chloro-4-fluorobenzyl)                       piperidine                                                                 1110 1 C(O) CH.sub.2 OCH.sub.3 4-benzylpiperidine                              1111 1 C(O) CH.sub.2 OCH.sub.3 3-acetyl-4-benzylpiperidine                     1112 1 C(O) CH.sub.2 OCH.sub.3 4-(3-fluorobenzyl)piperidine                    1113 1 C(O) CH.sub.2 OCH.sub.3 4-(4-fluorobenzyl)piperidine                    1114 1 C(O) CH.sub.2 OCH.sub.3 4-(2,3-difluorobenzyl)                              piperidine                                                                 1115 1 C(O) CH.sub.2 OCH.sub.3 4-(2-chloro-4-fluorobenzyl)                         piperidine                                                                 1116 1 C(O) CH.sub.2 CH.sub.2 - 4-benzylpiperidine                                tetrazolyl                                                                  1117 1 C(O) CH.sub.2 CH.sub.2 - 3-acetyl-4-benzylpiperidine                       tetrazolyl                                                                  1118 1 C(O) CH.sub.2 CH.sub.2 - 4-(3-fluorobenzyl)piperidine                      tetrazolyl                                                                  1119 1 C(O) CH.sub.2 CH.sub.2 - 4-(4-fluorobenzyl)piperidine                      tetrazolyl                                                                  1120 1 C(O) CH.sub.2 CH.sub.2 - 4-(2,3-difluorobenzyl)                            tetrazolyl piperidine                                                       1121 1 C(O) CH.sub.2 CH.sub.2 - 4-(2-chloro-4-fluorobenzyl)                       tetrazolyl piperidine                                                       1122 1 C(O)NH H 3-acetyl-4-benzylpiperidine                                    1123 1 C(O)NH H 4-(3-fluorobenzyl)piperidine                                   1124 1 C(O)NH H 4-(4-fluorobenzyl)piperidine                                   1125 1 C(O)NH H 4-(2,3-difluorobenzyl)                                             piperidine                                                                 1126 1 C(O)NH H 4-(2-chloro-4-fluorobenzyl)                                        piperidine                                                                 1127 1 C(O)NH CH.sub.2 CH.sub.2 OH 4-benzylpiperidine                          1128 1 C(O)NH CH.sub.2 CH.sub.2 OH 3-acetyl-4-benzylpiperidine                 1129 1 C(O)NH CH.sub.2 CH.sub.2 OH 4-(3-fluorobenzyl)piperidine                                             1130 1 C(O)NH CH.sub.2 CH.sub.2 OH                                            4-(4-fluorobenzyl)piperidine                       1131 1 C(O)NH CH.sub.2 CH.sub.2 OH 4-(2,3-difluorobenzyl)                          piperidine                                                                 1132 1 C(O)NH CH.sub.2 CH.sub.2 OH 4-(2-chloro-4-fluorobenzyl)                     piperidine                                                                 1133 1 C(O)NH CH.sub.2 OCH.sub.3 4-benzylpiperidine                            1134 1 C(O)NH CH.sub.2 OCH.sub.3 3-acetyl-4-benzylpiperidine                   1135 1 C(O)NH CH.sub.2 OCH.sub.3 4-(3-fluorobenzyl)piperidine                  1136 1 C(O)NH CH.sub.2 OCH.sub.3 4-(4-fluorobenzyl)piperidine                  1137 1 C(O)NH CH.sub.2 OCH.sub.3 4-(2,3-difluorobenzyl)                            piperidine                                                                 1138 1 C(O)NH CH.sub.2 OCH.sub.3 4-(2-chloro-4-fluorobenzyl)                       piperidine                                                                 1139 1 C(O)NH CH.sub.2 CH.sub.2 - 4-benzylpiperidine                              tetrazolyl                                                                  1140 1 C(O)NH CH.sub.2 CH.sub.2 - 3-acetyl-4-benzylpiperidine                     tetrazolyl                                                                  1141 1 C(O)NH CH.sub.2 CH.sub.2 - 4-(3-fluorobenzyl)piperidine                    tetrazolyl                                                                  1142 1 C(O)NH CH.sub.2 CH.sub.2 - 4-(4-fluorobenzyl)piperidine                    tetrazolyl                                                                  1143 1 C(O)NH CH.sub.2 CH.sub.2 - 4-(2,3-difluorobenzyl)                          tetrazolyl piperidine                                                       1144 1 C(O)NH CH.sub.2 CH.sub.2 - 4-(2-chloro-4-fluorobenzyl)                     tetrazolyl piperidine                                                       1145 1 SO.sub.2 NH H 4-benzylpiperidine                                        1146 1 SO.sub.2 NH H 3-acetyl-4-benzylpiperidine                               1147 1 SO.sub.2 NH H 4-(3-fluorobenzyl)piperidine                              1148 1 SO.sub.2 NH H 4-(4-fluorobenzyl)piperidine                              1149 1 SO.sub.2 NH H 4-(2,3-difluorobenzyl)                                        piperidine                                                                 1150 1 SO.sub.2 NH H 4-(2-chloro-4-fluorobenzyl)                                   piperidine                                                                 1151 1 SO.sub.2 NH CH.sub.2 CH.sub.2 OH 4-benzylpiperidine                     1152 1 SO.sub.2 NH CH.sub.2 CH.sub.2 OH 3-acetyl-4-benzylpiperidine                                         1153 1 SO.sub.2 NH CH.sub.2 CH.sub.2 OH                                       4-(3-fluorobenzyl)piperidine                       1154 1 SO.sub.2 NH CH.sub.2 CH.sub.2 OH 4-(4-fluorobenzyl)piperidine                                        1155 1 SO.sub.2 NH CH.sub.2 CH.sub.2 OH                                       4-(2,3-difluorobenzyl)                                 piperidine                                                                 1156 1 SO.sub.2 NH CH.sub.2 CH.sub.2 OH 4-(2-chloro-4-fluorobenzyl)                                             piperidine                                    1157 1 SO.sub.2 NH CH.sub.2 OCH.sub.3 4-benzylpiperidine                       1158 1 SO.sub.2 NH CH.sub.2 OCH.sub.3 3-acetyl-4-benzylpiperidine                                           1159 1 SO.sub.2 NH CH.sub.2 OCH.sub.3                                         4-(3-fluorobenzyl)piperidine                       1160 1 SO.sub.2 NH CH.sub.2 OCH.sub.3 4-(4-fluorobenzyl)piperidine                                          1161 1 SO.sub.2 NH CH.sub.2 OCH.sub.3                                         4-(2,3-difluorobenzyl)                                 piperidine                                                                 1162 1 SO.sub.2 NH CH.sub.2 OCH.sub.3 4-(2-chloro-4-fluorobenzyl)                                               piperidine                                    1163 1 SO.sub.2 NH CH.sub.2 CH.sub.2 - 4-benzylpiperidine                         tetrazolyl                                                                  1164 1 SO.sub.2 NH CH.sub.2 CH.sub.2 - 3-acetyl-4-benzylpiperidine                                             tetrazolyl                                     1165 1 SO.sub.2 NH CH.sub.2 CH.sub.2 - 4-(3-fluorobenzyl)piperidine                                            tetrazolyl                                     1166 1 SO.sub.2 NH CH.sub.2 CH.sub.2 - 4-(4-fluorobenzyl)piperidine                                            tetrazalyl                                     1167 1 SO.sub.2 NH CH.sub.2 CH.sub.2 - 4-(2,3-difluorobenzyl)                     tetrazolyl piperidine                                                       1168 1 SO.sub.2 NH CH.sub.2 CH.sub.2 - 4-(2-chloro-4-fluorobenzy1)                                             tetrazolyl piperidine                        ______________________________________                                    

                  TABLE 18                                                         ______________________________________                                           #STR50##                                                                       Ex     n      Z      R.sup.1  A-B                                            ______________________________________                                         1201 1      C(O)     H        4-benzylpiperidine                                 1202 1 C(O) H 3-acetyl-4-benzylpiperidine                                      1203 1 C(O) H 4-(3-fluorobenzyl)piperidine                                     1204 1 C(O) H 4-(4-fluorobenzyl)piperidine                                     1205 1 C(O) H 4-(2,3-difluorobenzyl)                                               piperidine                                                                 1206 1 C(O) H 4-(2-chloro-4-fluorobenzyl)                                          piperidine                                                                 1207 1 C(O) CH.sub.2 CH.sub.2 OH 4-benzylpiperidine                            1208 1 C(O) CH.sub.2 CH.sub.2 OH 3-acetyl-4-benzylpiperidine                   1209 1 C(O) CH.sub.2 CH.sub.2 OH 4-(3-fluorobenzyl)piperidine                  1210 1 C(O) CH.sub.2 CH.sub.2 OH 4-(4-fluorobenzyl)piperidine                  1211 1 C(O) CH.sub.2 CH.sub.2 OH 4-(2,3-difluorobenzyl)                            piperidine                                                                 1212 1 C(O) CH.sub.2 CH.sub.2 OH 4-(2-chloro-4-fluorobenzyl)                       piperidine                                                                 1213 1 C(O) CH.sub.2 OCH.sub.3 4-benzylpiperidine                              1214 1 C(O) CH.sub.2 OCH.sub.3 3-acetyl-4-benzylpiperidine                     1215 1 C(O) CH.sub.2 OCH.sub.3 4-(3-fluorobenzyl)piperidine                    1216 1 C(O) CH.sub.2 OCH.sub.3 4-(4-fluorobenzyl)piperidine                    1217 1 C(O) CH.sub.2 OCH.sub.3 4-(2,3-difluorobenzy1)                              piperidine                                                                 1218 1 C(O) CH.sub.2 OCH.sub.3 4-(2-chloro-4-fluorobenzyl)                         piperidine                                                                 1219 1 C(O) CH.sub.2 CH.sub.2 - 4-benzylpiperidine                                tetrazolyl                                                                  1220 1 C(O) CH.sub.2 CH.sub.2 - 3-acetyl-4-benzylpiperidine                       tetrazolyl                                                                  1221 1 C(O) CH.sub.2 CH.sub.2 - 4-(3-fluorobenzyl)piperidine                      tetrazolyl                                                                  1222 1 C(O) CH.sub.2 CH.sub.2 - 4-(4-fluorobenzyl)piperidine                      tetrazolyl                                                                  1223 1 C(O) CH.sub.2 CH.sub.2 - 4-(2,3-difluorobenzyl)                            tetrazolyl piperidine                                                       1224 1 C(O) CH.sub.2 CH.sub.2 - 4-(2-chloro-4-fluorobenzyl)                       tetrazolyl piperidine                                                       1225 1 C(O)NH H 4-benzylpiperidine                                             1226 1 C(O)NH H 3-acetyl-4-benzylpiperidine                                    1227 1 C(O)NH H 4-(3-fluorobenzyl)piperidine                                   1228 1 C(O)NH H 4-(4-fluorobenzyl)piperidine                                   1229 1 C(O)NH H 4-(2,3-difluorobenzyl)                                             piperidine                                                                 1230 1 C(O)NH H 4-(2-chloro-4-fluorobenzyl)                                        piperidine                                                                 1231 1 C(O)NH CH.sub.2 CH.sub.2 OH 4-benzylpiperidine                          1232 1 C(O)NH CH.sub.2 CH.sub.2 OH 3-acetyl-4-benzylpiperidine                 1233 1 C(O)NH CH.sub.2 CH.sub.2 OH 4-(3-fluorobenzyl)piperidine                                             1234 1 C(O)NH CH.sub.2 CH.sub.2 OH                                            4-(4-fluorobenzyl)piperidine                       1235 1 C(O)NH CH.sub.2 CH.sub.2 OH 4-(2,3-difluorobenzyl)                          piperidine                                                                 1236 1 C(O)NH CH.sub.2 CH.sub.2 OH 4-(2-chloro-4-fluorobenzyl)                     piperidine                                                                 1237 1 C(O)NH CH.sub.2 OCH.sub.3 4-benzylpiperidine                            1238 1 C(O)NH CH.sub.2 OCH.sub.3 3-acetyl-4-benzylpiperidine                   1239 1 C(O)NH CH.sub.2 OCH.sub.3 4-(3-fluorobenzyl)piperidine                  1240 1 C(O)NH CH.sub.2 OCH.sub.3 4-(4-fluorobenzyl)piperidine                  1241 1 C(O)NH CH.sub.2 OCH.sub.3 4-(2,3-difluorobenzyl)                            piperidine                                                                 1242 1 C(O)NH CH.sub.2 OCH.sub.3 4-(2-chloro-4-fluorobenzyl)                       piperidine                                                                 1243 1 C(O)NH CH.sub.2 CH.sub.2 - 4-benzylpiperidine                              tetrazolyl                                                                  1244 1 C(O)NH CH.sub.2 CH.sub.2 - 3-acetyl-4-benzylpiperidine                     tetrazolyl                                                                  1245 1 C(O)NH CH.sub.2 CH.sub.2 - 4-(3-fluorobenzyl)piperidine                    tetrazolyl                                                                  1246 1 C(O)NH CH.sub.2 CH.sub.2 - 4-(4-fluorobenzyl)piperidine                    tetrazolyl                                                                  1247 1 C(O)NH CH.sub.2 CH.sub.2 - 4-(2,3-difluorobenzyl)                          tetrazolyl piperidine                                                       1248 1 C(O)NH CH.sub.2 CH.sub.2 - 4-(2-chloro-4-fluorobenzyl)                     tetrazolyl piperidine                                                       1249 1 SO.sub.2 NH H 4-benzylpiperidine                                        1250 1 SO.sub.2 NH H 3-acetyl-4-benzylpiperidine                               1251 1 SO.sub.2 NH H 4-(3-fluorobenzyl)piperidine                              1252 1 SO.sub.2 NH H 4-(4-fluorobenzyl)piperidine                              1253 1 SO.sub.2 NH H 4-(2,3-difluorobenzyl)                                        piperidine                                                                 1254 1 SO.sub.2 NH H 4-(2-chloro-4-fluorobenzyl)                                   piperidine                                                                 1255 1 SO.sub.2 NH CH.sub.2 CH.sub.2 OH 4-benzylpiperidine                     1256 1 SO.sub.2 NH CH.sub.2 CH.sub.2 OH 3-acetyl-4-benzylpiperidine                                         1257 1 SO.sub.2 NH CH.sub.2 CH.sub.2 OH                                       4-(3-fluorobenzyl)piperidine                       1258 1 SO.sub.2 NH CH.sub.2 CH.sub.2 OH 4-(4-fluorobenzyl)piperidine                                        1259 1 SO.sub.2 NH CH.sub.2 CH.sub.2 OH                                       4-(2,3-difluorobenzyl)                                 piperidine                                                                 1260 1 SO.sub.2 NH CH.sub.2 CH.sub.2 OH 4-(2-chloro-4-fluorobenzyl)                                             piperidine                                    1261 1 SO.sub.2 NH CH.sub.2 OCH.sub.3 4-benzylpiperidine                       1262 1 SO.sub.2 NH CH.sub.2 OCH.sub.3 3-acetyl-4-benzylpiperidine                                           1263 1 SO.sub.2 NH CH.sub.2 OCH.sub.3                                         4-(3-fluorobenzyl)piperidine                       1264 1 SO.sub.2 NH CH.sub.2 OCH.sub.3 4-(4-fluorobenzyl)piperidine                                          1265 1 SO.sub.2 NH CH.sub.2 OCH.sub.3                                         4-(2,3-difluorobenzyl)                                 piperidine                                                                 1266 1 SO.sub.2 NH CH.sub.2 OCH.sub.3 4-(2-chloro-4-fluorobenzyl)                                               piperidine                                    1267 1 SO.sub.2 NH CH.sub.2 CH.sub.2 - 4-benzylpiperidine                         tetrazolyl                                                                  1268 1 SO.sub.2 NH CH.sub.2 CH.sub.2 - 3-acetyl-4-benzylpiperidine                                             tetrazolyl                                     1269 1 SO.sub.2 NH CH.sub.2 CH.sub.2 - 4-(3-fluorobenzyl)piperidifle                                           tetrazolyl                                     1270 1 SO.sub.2 NH CH.sub.2 CH.sub.2 - 4-(4-fluorobenzyl)piperidine                                            tetrazolyl                                     1271 1 SO.sub.2 NH CH.sub.2 CH.sub.2 - 4-(2,3-difluorobenzyl)                     tetrazolyl piperidine                                                       1272 1 SO.sub.2 NH CH.sub.2 CH.sub.2 - 4-(2-chloro-4-fluorobenzyl)                                             tetrazolyl piperidine                        ______________________________________                                    

                  TABLE 19                                                         ______________________________________                                           #STR51##                                                                       Ex     n      Z      R.sup.1  A-B                                            ______________________________________                                         1301 1      C(O)     H        4-benzylpiperidine                                 1302 1 C(O) H 3-acetyl-4-benzylpiperidine                                      1303 1 C(O) H 4-(3-fluorobenzyl)piperidine                                     1304 1 C(O) H 4-(4-fluorobenzyl)piperidine                                     1305 1 C(O) H 4-(2,3-difluorobenzyl)                                               piperidine                                                                 1306 1 C(O) H 4-(2-chloro-4-fluorobenzyl)                                          piperidine                                                                 1307 1 C(O) CH.sub.2 CH.sub.2 OH 4-benzylpiperidine                            1308 1 C(O) CH.sub.2 CH.sub.2 OH 3-acetyl-4-benzylpiperidine                   1309 1 C(O) CH.sub.2 CH.sub.2 OH 4-(3-fluorobenzyl)piperidine                  1310 1 C(O) CH.sub.2 CH.sub.2 OH 4-(4-fluorobenzyl)piperidine                  1311 1 C(O) CH.sub.2 CH.sub.2 OH 4-(2,3-difluorobenzyl)                            piperidine                                                                 1312 1 C(O) CH.sub.2 CH.sub.2 OH 4-(2-chloro-4-fluorobenzyl)                       piperidine                                                                 1313 1 C(O) CH.sub.2 OCH.sub.3 4-benzylpiperidine                              1314 1 C(O) CH.sub.2 OCH.sub.3 3-acetyl-4-benzylpiperidine                     1315 1 C(O) CH.sub.2 OCH.sub.3 4-(3-fluorobenzyl)piperidine                    1316 1 C(O) CH.sub.2 OCH.sub.3 4-(4-fluorobenzyl)piperidine                    1317 1 C(O) CH.sub.2 OCH.sub.3 4-(2,3-difluorobenzyl)                              piperidine                                                                 1318 1 C(O) CH.sub.2 OCH.sub.3 4-(2-chloro-4-fluorobenzyl)                         piperidine                                                                 1319 1 C(O) CH.sub.2 CH.sub.2 - 4-benzylpiperidine                                tetrazolyl                                                                  1320 1 C(O) CH.sub.2 CH.sub.2 - 3-acetyl-4-benzylpiperidine                       tetrazolyl                                                                  1321 1 C(O) CH.sub.2 CH.sub.2 - 4-(3-fluorobenzyl)piperidine                      tetrazolyl                                                                  1322 1 C(O) CH.sub.2 CH.sub.2 - 4-(4-fluorobenzyl)piperidine                      tetrazolyl                                                                  1323 1 C(O) CH.sub.2 CH.sub.2 - 4-(2,3-difluorobenzyl)                            tetrazolyl piperidine                                                       1324 1 C(O) CH.sub.2 CH.sub.2 - 4-(2-chloro-4-fluorobenzyl)                       tetrazolyl piperidine                                                       1325 1 C(O)NH H 4-benzylpiperidine                                             1326 1 C(O)NH H 3-acetyl-4-benzylpiperidine                                    1327 1 C(O)NH H 4-(3-fluorobenzyl)piperidine                                   1328 1 C(O)NH H 4-(4-fluorobenzyl)piperidine                                   i329 1 C(O)NH H 4-(2,3-difluorobenzyl)                                             piperidine                                                                 1330 1 C(O)NH H 4-(2-chloro-4-fluorobenzyl)                                        piperidine                                                                 1331 1 C(O)NH CH.sub.2 CH.sub.2 OH 4-benzylpiperidine                          1332 1 C(O)NH CH.sub.2 CH.sub.2 OH 3-acetyl-4-benzylpiperidine                 1333 1 C(O)NH CH.sub.2 CH.sub.2 OH 4-(3-fluorobenzyl)piperidine                                             1334 1 C(O)NH CH.sub.2 CH.sub.2 OH                                            4-(4-fluorobenzyl)piperidine                       1335 1 C(O)NH CH.sub.2 CH.sub.2 OH 4-(2,3-difluorobenzyl)                          piperidine                                                                 1336 1 C(O)NH CH.sub.2 CH.sub.2 OH 4-(2-chloro-4-fluorobenzyl)                     piperidine                                                                 1337 1 C(O)NH CH.sub.2 OCH.sub.3 4-benzylpiperidine                            1338 1 C(O)NH CH.sub.2 OCH.sub.3 3-acetyl-4-benzylpiperidine                   1339 1 C(O)NH CH.sub.2 OCH.sub.3 4-(3-fluorobenzyl)piperidine                  1340 1 C(O)NH CH.sub.2 OCH.sub.3 4-(4-fluorobenzyl)piperidine                  1341 1 C(O)NH CH.sub.2 OCH.sub.3 4-(2,3-difluorobenzyl)                            piperidine                                                                 1342 1 C(O)NH CH.sub.2 OCH.sub.3 4-(2-chloro-4-fluorobenzyl)                       piperidine                                                                 1343 1 C(O)NH CH.sub.2 CH.sub.2 - 4-benzylpiperidine                              tetrazolyl                                                                  1344 1 C(O)NH CH.sub.2 CH.sub.2 - 3-acetyl-4-benzylpiperidine                     tetrazolyl                                                                  1345 1 C(O)NH CH.sub.2 CH.sub.2 - 4-(3-fluorobenzyl)piperidine                    tetrazolyl                                                                  1346 1 C(O)NH CH.sub.2 CH.sub.2 - 4-(4-fluorobenzyl)piperidine                    tetrazolyl                                                                  1347 1 C(O)NH CH.sub.2 CH.sub.2 - 4-(2,3-difluorobenzyl)                          tetrazolyl piperidine                                                       1348 1 C(O)NH CH.sub.2 CH.sub.2 - 4-(2-chloro-4-fluorobenzyl)                     tetrazolyl piperidine                                                       1349 1 SO.sub.2 NH H 4-benzylpiperidine                                        1350 1 SO.sub.2 NH H 3-acetyl-4-benzylpiperidine                               1351 1 SO.sub.2 NH H 4-(3-fluorobenzyl)piperidine                              1352 1 SO.sub.2 NH H 4-(4-fluorobenzyl)piperidine                              1353 1 SO.sub.2 NH H 4-(2,3-difluorobenzyl)                                        piperidine                                                                 1354 1 SO.sub.2 NH H 4-(2-chloro-4-fluorobenzyl)                                   piperidine                                                                 1355 1 SO.sub.2 NH CH.sub.2 CH.sub.2 OH 4-benzylpiperidine                     1356 1 SO.sub.2 NH CH.sub.2 CH.sub.2 OH 3-acetyl-4-benzylpiperidine                                         1357 1 SO.sub.2 NH CH.sub.2 CH.sub.2 OH                                       4-(3-fluorobenzyl)piperidine                       1358 1 SO.sub.2 NH CH.sub.2 CH.sub.2 OH 4-(4-fluorobenzyl)piperidine                                        1359 1 SO.sub.2 NH CH.sub.2 CH.sub.2 OH                                       4-(2,3-difluorobenzyl)                                 piperidine                                                                 1360 1 SO.sub.2 NH CH.sub.2 CH.sub.2 OH 4-(2-chloro-4-fluorobenzyl)                                             piperidine                                    1361 1 SO.sub.2 NH CH.sub.2 OCH.sub.3 4-benzylpiperidine                       1362 1 SO.sub.2 NH CH.sub.2 CCH.sub.3 3-acetyl-4-benzylpiperidine                                           1363 1 SO.sub.2 NH CH.sub.2 OCH.sub.3                                         4-(3-fluorobenzyl)piperidine                       1364 1 SO.sub.2 NH CH.sub.2 OCH.sub.3 4-(4-fluorobenzyl)piperidine                                          1365 1 SO.sub.2 NH CH.sub.2 OCH.sub.3                                         4-(2,3-difluorobenzyl)                                 piperidine                                                                 1366 1 SO.sub.2 NH CH.sub.2 OCH.sub.3 4-(2-chloro-4-fluorobenzyl)                                               piperidine                                    1367 1 SO.sub.2 NH CH.sub.2 CH.sub.2 - 4-benzylpiperidine                         tetrazolyl                                                                  1368 1 SO.sub.2 NH CH.sub.2 CH.sub.2 - 3-acetyl-4-benzylpiperidine                                             tetrazolyl                                     1369 1 SO.sub.2 NH CH.sub.2 CH.sub.2 - 4-(3-fluorobenzyl)piperidine                                            tetrazolyl                                     1370 1 SO.sub.2 NH CH.sub.2 CH.sub.2 - 4-(4-fluorobenzyl)piperidine                                            tetrazolyl                                     1371 1 SO.sub.2 NH CH.sub.2 CH.sub.2 - 4-(2,3-difluorobenzyl)                     tetrazolyl piperidine                                                       1372 1 SO.sub.2 NH CH.sub.2 CH.sub.2 - 4-(2-chloro-4-fluorobenzyl)                                             tetrazolyl piperidine                        ______________________________________                                    

                  TABLE 20                                                         ______________________________________                                           #STR52##                                                                       Ex     n      Z             A-B                                              ______________________________________                                         1401 1      C(O)            4-(2-                                                   aminosulfonylphenyl)phenyl                                                  1402 1 C(O) 4-(2-aminosulfonylphenyl)-2-                                          pyridyl                                                                     1403 1 C(O) 4-(2-methylaminosulfonyl-                                             phenyl)phenyl                                                               1404 1 C(O) 4-(2-ethylaminosulfonyl-                                              phenyl)-2-pyridyl                                                           1405 1 C(O) 2-aminosulfonyl-4-                                                    cyclohexylphenyl                                                            1406 1 C(O) 3-aminosulfonyl-4-t-butyl-2-                                          pyridyl                                                                     1407 1 C(O) 2-(5-indazol-5-yl)furanyl                                          1408 1 C(O) 2-(5-indazol-6-yl)thienyl                                          1409 1 C(O) 4-(2-tetrazolylphenyl)phenyl                                       1410 1 C(O)NH 4-(2-                                                               aminosulfonylphenyl)phenyl                                                  1411 1 C(O)NH 4-(2-aminosulfonylphenyl)-2-                                        pyridyl                                                                     1412 1 C(O)NH 4-(2-methylaminosulfonyl-                                           phenyl)phenyl                                                               1413 1 C(O)NH 4-(2-ethylaminosulfonyl-                                            phenyl)-2-pyridyl                                                           1414 1 C(O)NH 2-aminosulfonyl-4-                                                  cyclohexylphenyl                                                            1415 1 C(O)NH 3-aminosulfonyl-4-t-butyl-2-                                        pyridyl                                                                     1416 1 C(O)NH 2-(5-indazol-5-yl)furanyl                                        1417 1 C(O)NH 2-(5-indazol-6-yl)thienyl                                        1418 1 C(O)NH 4-(2-tetrazolylphenyl)phenyl                                     1419 1 NHC(O) 4-(2-                                                               aminosulfonylphenyl)phenyl                                                  1420 1 NHC(O) 4-(2-aminosulfonylphenyl)-2-                                        pyridyl                                                                     1421 1 NHC(O) 4-(2-methylaminosulfonyl-                                           phenyl)phenyl                                                               1422 1 NHC(O) 4-(2-ethylaminosulfonyl-                                            phenyl)-2-pyridyl                                                           1423 1 NHC(O) 2-aminosulfonyl-4-                                                  cyclohexylphenyl                                                            1424 1 NHC(O) 3-aminosulfonyl-4-t-butyl-2-                                        pyridyl                                                                     1425 1 NHC(O) 2-(5-indazol-5-yl)furanyl                                        1426 1 NHC(O) 2-(5-indazol-6-yl)thienyl                                        1427 1 NHC(O) 4-(2-tetrazolylphenyl)phenyl                                     1428 1 SO.sub.2 NH 4-(2-                                                          aminosulfonylphenyl)phenyl                                                  1429 1 SO.sub.2 NH 4-(2-aminosulfonylphenyl)-2-                                   pyridyl                                                                     1430 1 SO.sub.2 NH 4-(2-methylaminosulfonyl-                                      phenyl)phenyl                                                               1431 1 SO.sub.2 NH 4-(2-ethylaminosulfonyl-                                       phenyl)-2-pyridyl                                                           1432 1 SO.sub.2 NH 2-aminosulfonyl-4-                                             cyclohexylphenyl                                                            1433 1 SO.sub.2 NH 3-aminosulfonyl-4-t-butyl-2-                                   pyridyl                                                                     1434 1 SO.sub.2 NH 2-(5-indazol-5-yl)furanyl                                   1435 1 SO.sub.2 NH 2-(5-indazol-6-yl)thienyl                                   1436 1 SO.sub.2 NH 4-(2-tetrazolylphenyl)phenyl                                1437 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-                                       aminosulfonylphenyl)phenyl                                                  1438 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-aminosulfonylphenyl)-2-                                           pyridyl                                          1439 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-methylaminosulfonyl-                                              phenyl)phenyl                                    1440 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-ethylaminosulfonyl-                    phenyl)-2-pyridyl                                                           1441 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-aminosulfonyl-4-                          cyclohexylphenyl                                                            1442 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 3-aminosulfonyl-4-t-butyl-2-                                           pyridyl                                          1443 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 2-(5-indazol-5-yl)furanyl                                           1444 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH                                         2-(5-indazol-6-yl)thienyl                            1445 0 CH(CH.sub.2 CH.sub.2 OH)C(O)NH 4-(2-tetrazolylphenyl)phenyl                                        1446 0 CH(CH.sub.2 - 4-(2-                            tetrazolyl)C(O)NH aminosulfonylphenyl)phenyl                                 1447 0 CH(CH.sub.2 - 4-(2-aminosulfonylphenyl)-2-                                tetrazolyl)C(O)NH pyridyl                                                    1448 0 CH(CH.sub.2 - 4-(2-methylaminosulfonyl-                                   tetrazolyl)C(O)NH phenyl)phenyl                                              1449 0 CH(CH.sub.2 - 4-(2-ethylaminosulfonyl-                                    tetrazolyl)C(O)NH phenyl)-2-pyridyl                                          1450 0 CH(CH.sub.2 - 2-aminosulfonyl-4-                                          tetrazolyl)C(O)NH cyclohexylphenyl                                           1451 0 CH(CH.sub.2 - 3-aminosulfonyl-4-t-butyl-2-                                tetrazolyl)C(O) NH pyridyl                                                   1452 0 CH(CH.sub.2 - 2-(5-indazol-5-yl)furanyl                                   tetrazolyl)C(O)NH                                                            1453 0 CH(CH.sub.2 - 2-(5-indazol-6-yl)thienyl                                   tetrazolyl)C(O)NH                                                            1454 0 CH(CH.sub.2 - 4-(2-tetrazolylphenyl)phenyl                                tetrazolyl)C(O)NH                                                          ______________________________________                                    

                  TABLE 21                                                         ______________________________________                                           #STR53##                                                                       Ex        Z'            A-B                                                  ______________________________________                                         1501    CH.sub.2 C(O)NH                                                                              4-(2-                                                        aminosulfonylphenyl)phenyl                                                   1502 CH.sub.2 C(O)NH 4-(2-aminosulfonylphenyl)-2-                                pyridyl                                                                      1503 CH.sub.2 C(O)NH 4-(2-methylaminosulfonyl-                                   phenyl)phenyl                                                                1504 CH.sub.2 C(O)NH 4-(2-ethylaminosulfonyl-                                    phenyl)-2-pyridyl                                                            1505 CH.sub.2 C(O)NH 2-aminosulfonyl-4-                                          cyclohexylphenyl                                                             1506 CH.sub.2 C(O)NH 3-aminosulfonyl-4-t-butyl-2-                                pyridyl                                                                      1507 CH.sub.2 C(O)NH 2-(5-indazol-5-yl)furanyl                                 1508 CH.sub.2 C(O)NH 2-(5-indazol-6-yl)thienyl                                 1509 CH.sub.2 C(O)NH 4-(2-tetrazolylphenyl)phenyl                              1510 CH.sub.2 CH.sub.2 C(O)NH 4-(2-                                              aminosulfonylphenyl)phenyl                                                   1511 CH.sub.2 CH.sub.2 C(O)NH 4-(2-aminosulfonylphenyl)-2-                       pyridyl                                                                      1512 CH.sub.2 CH.sub.2 C(O)NH 4-(2-tert-butylaminosulfonyl-                      phenyl)phenyl                                                                1513 CH.sub.2 CH.sub.2 C(O)NH 4-(2-ethylaminosulfonyl-                           phenyl)-2-pyridyl                                                            1514 CH.sub.2 CH.sub.2 C(O)NH 2-aminosulfonyl-4-                                 cyclohexylphenyl                                                             1515 CH.sub.2 CH.sub.2 C(O)NH 3-aminosulfonyl-4-t-butyl-2                        pyridyl                                                                      1516 CH.sub.2 CH.sub.2 C(O)NH 2-(5-indazol-5-yl)furanyl                        1517 CH.sub.2 CH.sub.2 C(O)NH 2-(5-indazol-6-yl)thienyl                        1518 CH.sub.2 CH.sub.2 C(O)NH 4-(2-tetrazolylphenyl)phenyl                     1519 SCH.sub.2 C(O)NH 4-(2-                                                      aminosulfonylphenyl)phenyl                                                   1520 SCH.sub.2 C(O)NH 4-(2-aminosulfonylphenyl)-2-                               pyridyl                                                                      1521 SCH.sub.2 C(O)NH 4-(2-methylaminosulfonyl-                                  phenyl)phenyl                                                                1522 SCH.sub.2 C(O)NH 4-(2-ethylaminosulfonyl-                                   phenyl)-2-pyridyl                                                            1523 SCH.sub.2 C(O)NH 2-aminosulfonyl-4-                                         cyclohexylphenyl                                                             1524 SCH.sub.2 C(O)NH 3-aminosulfonyl-4-t-butyl-2-                               pyridyl                                                                      1525 SCH.sub.2 C(O)NH 2-(5-indazol-5-yl)furanyl                                1526 SCH.sub.2 C(O)NH 2-(5-indazol-6-yl) thienyl                               1527 SCH.sub.2 C(O)NH 4-(2-tetrazolylphenyl)phenyl                           ______________________________________                                    

UTILITY

The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term "thromboembolic disorders" as used herein includes arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, cerebral embolism, kidney embolisms, and pulmonary embolisms. The anticoagulant effect of compounds of the present invention is believed to be due to inhibition of factor Xa or thrombin.

The effectiveness of compounds of the present invention as inhibitors of factor Xa was determined using purified human factor Xa and synthetic substrate. The rate of factor Xa hydrolysis of chromogenic substrate S2222 (Kabi Pharmacia, Franklin, Ohio) was measured both in the absence and presence of compounds of the present invention. Hydrolysis of the substrate resulted in the release of pNA, which was monitored spectrophotometrically by measuring the increase in absorbance at 405 nM. A decrease in the rate of absorbance change at 405 nm in the presence of inhibitor is indicative of enzyme inhibition. The results of this assay are expressed as inhibitory constant, K_(i).

Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH 7.5, containing 0.20 M NaCl, and 0.5% PEG 8000. The Michaelis constant, K_(m), for substrate hydrolysis was determined at 25° C. using the method of Lineweaver and Burk. Values of K_(i) were determined by allowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend, Ind.) to react with the substrate (0.20 mM-1 mM) in the presence of inhibitor. Reactions were allowed to go for 30 minutes and the velocities (rate of absorbance change vs time) were measured in the time frame of 25-30 minutes. The following relationship was used to calculate K_(i) values:

    (v.sub.o -v.sub.s)/v.sub.s =I/(K.sub.i (1+S/K.sub.m))

where:

v_(o) is the velocity of the control in the absence of inhibitor;

v_(s) is the velocity in the presence of inhibitor;

I is the concentration of inhibitor;

K_(i) is the dissociation constant of the enzyme:inhibitor complex;

S is the concentration of substrate;

K_(m) is the Michaelis constant.

Using the methodology described above, a number of compounds of the present invention were found to exhibit a K_(i) of ≦5 μm, thereby confirming the utility of the compounds of the present invention as effective Xa inhibitors.

The antithrombotic effect of compounds of the present invention can be demonstrated in a rabbit arterio-venous (AV) shunt thrombosis model. In this model, rabbits weighing 2-3 kg anesthetized with a mixture of xylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used. A saline-filled AV shunt device is connected between the femoral arterial and the femoral venous cannulae. The AV shunt device consists of a piece of 6-cm tygon tubing which contains a piece of silk thread. Blood will flow from the femoral artery via the AV-shunt into the femoral vein. The exposure of flowing blood to a silk thread will induce the formation of a significant thrombus. After forty minutes, the shunt is disconnected and the silk thread covered with thrombus is weighed. Test agents or vehicle will be given (i.v., i.p., s.c., or orally) prior to the opening of the AV shunt. The percentage inhibition of thrombus formation is determined for each treatment group. The ID50 values (dose which produces 50% inhibition of thrombus formation) are estimated by linear regression.

The compounds of formula (I) are also considered to be useful as inhibitors of serine proteases, notably human thrombin, plasma kallikrein and plasmin. Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation, catalyzed by the aforesaid class of enzymes. Specifically, the compounds have utility as drugs for the treatment of diseases arising from elevated thrombin activity such as myocardial infarction, and as reagents used as anticoagulants in the processing of blood to plasma for diagnostic and other commercial purposes.

Some compounds of the present invention were shown to be direct acting inhibitors of the serine protease thrombin by their ability to inhibit the cleavage of small molecule substrates by thrombin in a purified system. In vitro inhibition constants were determined by the method described by Kettner et al. in J. Biol. Chem. 265, 18289-18297 (1990), herein incorporated by reference. In these assays, thrombin-mediated hydrolysis of the chromogenic substrate S2238 (Helena Laboratories, Beaumont, Tex.) was monitored spectrophotometrically. Addition of an inhibitor to the assay mixture results in decreased absorbance and is indicative of thrombin inhibition. Human thrombin (Enzyme Research Laboratories, Inc., South Bend, Ind.) at a concentration of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000, was incubated with various substrate concentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minutes of incubation, thrombin activity was assayed by monitoring the rate of increase in absorbance at 405 nm which arises owing to substrate hydrolysis. Inhibition constants were derived from reciprocal plots of the reaction velocity as a function of substrate concentration using the standard method of Lineweaver and Burk. Using the methodology described above, some compounds of this invention were evaluated and found to exhibit a K_(i) of less than 5 μm, thereby confirming the utility of the compounds of the invention as effective thrombin inhibitors.

The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. These include other anti-coagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, or thrombolytic or fibrinolytic agents.

The compounds are administered to a mammal in a therapeutically effective amount. By "therapeutically effective amount" it is meant an amount of a compound of Formula I that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.

By "administered in combination" or "combination therapy" it is meant that the compound of Formula I and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. Other anticoagulant agents (or coagulation inhibitory agents) that may be used in combination with the compounds of this invention include warfarin and heparin, as well as other factor Xa inhibitors such as those described in the publications identified above under Background of the Invention.

The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include, but are not limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA), and piroxicam are preferred. Other suitable anti-platelet agents include ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use. Still other suitable platelet inhibitory agents include IIb/IIIa antagonists, thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.

The term thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted. A number of thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination with the present compounds. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal a-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitors include compounds described in Kettner et al., U.S. Pat. No. 5,187,157 and European Patent Application Publication Number 293 881 A2, the disclosures of which are hereby incorporated herein by reference. Other suitable boroarginine derivatives and boropeptide thrombin inhibitors include those disclosed in PCT Application Publication Number 92/07869 and European Patent Application Publication Number 471,651 A2, the disclosures of which are hereby incorporated herein by reference.

The term thrombolytics (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosure of which is hereby incorporated herein by reference herein. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.

Administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.

The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the inhibition of factor Xa. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving factor Xa. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnostic assays involving factor Xa. For example, the presence of factor Xa in an unknown sample could be determined by addition of chromogenic substrate S2222 to a series of solutions containing test sample and optionally one of the compounds of the present invention. If production of pNA is observed in the solutions containing test sample, but no compound of the present invention, then one would conclude factor Xa was present.

DOSAGE AND FORMULATION

The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

Representative useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.

Tablets

A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

Injectable

A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.

Suspension

An aqueous suspension is prepared for oral administration so that each 5 mL contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mL of vanillin.

Where the compounds of this invention are combined with other anticoagulant agents, for example, a daily dosage may be about 0.1 to 100 milligrams of the compound of Formula I and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight. For a tablet dosage form, the compounds of this invention generally may be present in an amount of about 5 to 10 milligrams per dosage unit, and the second anti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.

Where the compounds of Formula I are administered in combination with an anti-platelet agent, by way of general guidance, typically a daily dosage may be about 0.01 to 25 milligrams of the compound of Formula I and about 50 to 150 milligrams of the anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight.

Where the compounds of Formula I are adminstered in combination with thrombolytic agent, typically a daily dosage may be about 0.1 to 1 milligrams of the compound of Formula I, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 70-80% when administered with a compound of Formula I.

Where two or more of the foregoing second therapeutic agents are administered with the compound of Formula I, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.

Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of Formula I and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.

Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein. 

What is claimed as new and desired to be secured by Letter Patent of United States is:
 1. A compound of formula I: ##STR54## or stereoisomer or pharmaceutically acceptable salt form thereof wherein: W and W³ are CH;W¹ and W² are selected from C and CH; one of D and D^(a) is selected from CN, C(═NR⁷)NR⁸ R⁹, NHC(═NR⁷)NR⁸ R⁹, NR⁸ CH(═NR⁷), C(O)NR⁸ R⁹, and (CH₂)_(t) NR⁸ R⁹, and the other is absent; one of J^(a) and J^(b) is substituted by --(CH₂)_(n) --Z--A--B; J, J^(a), and J^(b) combine to form pyrazole substituted with 0-2 R¹ ; R¹ is selected from H, C₁₋₄ alkyl, (CH₂)_(r) OR³, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) C(═O)R², (CH₂)_(r) (CH═CH)(CH₂)_(r) C(═O)R², (CH₂)_(r) NR³ C(O)R², (CH₂)_(r) SO₂ R⁴, (CH₂)_(r) NR³ SO₂ R⁴, and (CH₂)_(r) -5-membered heterocyclic group having 1-4 heteroatoms selected from N, O, and S; R² is selected from H, OR³, C₁₋₄ alkyl, NR³ R^(3'), CF₃, and C₃₋₁₀ carbocyclic group substituted with 0-2 R⁶ ; R³ and R^(3') are independently selected from H, C₁₋₄ alkyl, and C₃₋₁₀ carbocyclic group substituted with 0-2 R⁶ ; R⁴ is selected from C₁₋₄ alkyl, NR³ R^(3'), and C₃₋₁₀ carbocyclic group substituted with 0-2 R⁶ ; Z is selected from CH═CH, CH((CH₂)_(m) Q(CH₂)_(m) R⁵), CH((CH₂)_(m) Q(CH₂)_(m) R⁵)C(O)NR³, CH((CH₂)_(m) C(O)(CH₂)_(m) R^(5a)), N((CH₂)_(q) Q(CH₂)_(m) R⁵), N(Q'(CH₂)_(m) R⁵), C(O)N((CH₂)_(m) Q'(CH₂)_(m) R^(5a)), C(O)(CH₂)_(r), C(O)O(CH₂)_(r), OC(O)(CH₂)_(r), C(O)(CH₂)_(r) NR³ (CH₂)_(r), NR³ C(O)(CH₂)_(r), OC(O)NR³ (CH₂)_(r), NR³ C(O)O(CH₂)_(r), NR³ C(O)NR³ (CH₂)_(r), S(O)_(p) (CH₂)_(r), SO₂ CH₂, SCH₂ C(O)NR³, SO₂ NR³ (CH₂)_(r), NR³ SO₂ (CH₂)_(r), and NR³ SO₂ NR³ (CH₂)_(r) ; Q is selected from a bond, O, NR³, C(O), C(O)NR³, NR³ C(O), SO₂, NR³ SO₂, and SO₂ NR³ ; Q' is selected from a bond, C(O), C(O)NR³, SO₂, and SO₂ NR³ ; R⁵ is selected from H, C₁₋₄ alkyl, C₃₋₁₀ carbocyclic group substituted with 0-2 R⁶, and 5-10 membered heterocyclic group containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶, provided that when Q is SO₂ or NR³ SO₂, R⁵ is other than H and when Q' is SO₂, R⁵ is other than H; R^(5a) is selected from NHR⁵, OR⁵, and R⁵ ; A is pyridine substituted with 0-2 R⁶ ; B is selected from:X--Y, C₃₋₆ alkyl, NR³ R^(3'), C(═NR³)NR³ R^(3'), NR³ C(═NR³)NR³ R^(3'), benzyl substituted with 0-2 R⁶, C₃₋₁₀ carbocyclic group substituted with 0-2 R⁶, and - 10membered heterocyclic group containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ; X is selected from C₁₋₄ alkylene, --C(O)--, --C(O)CR³ R^(3') --, --CR³ R^(3') C(O), --S(O)_(p) --, --S(O)_(p) CR³ R^(3') --, --CR³ R^(3') S(O)_(p) --, --S(O)₂ NR³ --, --NR³ S(O)₂ --, --C(O)NR³ --, --NR³ C(O)--, --NR³ --, --NR³ CR³ R^(3') --, --CR³ R^(3') NR³ --, O, --CR³ R^(3') O--, and --OCR³ R^(3') --; Y is selected from:C₃₋₁₀ carbocyclic group substituted with 0-2 R⁶, and - 10membered heterocyclic group containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ; R⁶ is selected from H, OH, (CH₂)_(n) OR³, halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) C(O)R³, NR³ C(O)R^(3'), NR³ C(O)NR³ R^(3'), CH(═NH)NH₂, NHC(═NH)NH₂, SO₂ NR³ R^(3'), CONHSO₂ R⁴, NR³ SO₂ NR³ R.sup.^(3'), NR³ SO₂ --C₁₋₄ alkyl, and (C₁₋₄ alkyl)-tetrazolyl; R⁷ is selected from H, OH, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl; R⁸ is selected from H, C₁₋₆ alkyl and (CH₂)_(n) -phenyl; R⁹ is selected from H, C₁₋₆ alkyl and (CH₂)_(n) -phenyl; n is selected from 0, 1, 2, 3, and 4; m is selected from 0, 1, and 2; p is selected from 0, 1, and 2; q is selected from 1 and 2; and, r is selected from 0, 1, 2, 3, and 4;provided that: (a) Z is other than CH₂ ; and, (b) if Z is CH((CH₂)_(m) Q(CH₂)_(m) R⁵) or CH((CH₂)_(m) C(O)(CH₂)_(m) R^(5a)), then B is other than X--Y, a C₃₋₁₀ carbocyclic group or a 5-10 membered heterocyclic group; (c) R⁵, B, and Y are other than piperazine and piperidine.
 2. A compound according to claim 1, wherein the compound is of formula II: ##STR55## or a stereoisomer or pharmaceutically acceptable salt, wherein: R¹ is selected from H, C₁₋₄ alkyl, (CH₂)_(r) OR³, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) C(═O)R², (CH₂)_(r) NR³ C(═O)R², (CH₂)_(r) SO₂ R⁴, (CH₂)_(r) NR³ SO₂ R⁴, and (CH₂)_(r) -5-membered heterocyclic group having 1-4 heteroatoms selected from N, O, and S;R² is selected from H, OR³, C₁₋₄ alkyl, NR³ R^(3'), and CF₃ ; R³ and R^(3') are independently selected from H, C₁₋₄ alkyl, and phenyl; R⁴ is selected from C₁₋₄ alkyl, phenyl and NR³ R^(3') ; Z is selected from CH═CH, CH((CH₂)_(m) Q(CH₂)_(m) R⁵), CH((CH₂)_(m) Q(CH₂)_(m) R⁵)C(O)NR³, CH((CH₂)_(m) C(O)(CH₂)_(m) R^(5a)), N((CH₂)_(q) Q(CH₂)_(m) R⁵), N(Q'(CH₂)_(m) R⁵), C(O)N((CH₂)_(m) Q'(CH₂)_(m) R^(5a)), C(O), C(O)CH₂, C(O)O, OC(O), C(O)(CH₂)_(r) NR³ (CH₂)_(r), NR³ C(O), OC(O)NR³, NR³ C(O)O, NR³ C(O)NR³, S(O)_(p), SO₂ CH₂, SO₂ NR³, NR³ SO₂, and NR³ SO₂ NR³ ; B is selected from:X--Y, C₃₋₆ alkyl, benzyl substituted with 0-2 R⁶, C₃₋₁₀ carbocyclic group substituted with 0-2 R⁶, and 5-10 membered heterocyclic group containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ; and, R⁶ is selected from H, OH, (CH₂)_(n) OR³, halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) C(O)R³, NR³ C(O)R^(3'), NR³ C(O)NR³ R^(3'), SO₂ NR³ R^(3'), CONHSO₂ R⁴, NR³ SO₂ NR³ R^(3'), NR³ SO₂ --C₁₋₄ alkyl and (C₁₋₄ alkyl)-tetrazolyl.
 3. A compound according to claim 2, wherein:R¹ is selected from H, C₁₋₄ alkyl, (CH₂)_(r) OR³, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) C(═O)R², (CH₂)_(r) NR³ C(═O )R², (CH₂)_(r) SO₂ R⁴, and (CH₂)_(r) NR³ SO₂ R⁴ ; Z is selected from CH((CH₂)_(m) Q(CH₂)_(m) R⁵), CH((CH₂)_(m) Q(CH₂)_(m) R⁵)C(O)NR³, CH((CH₂)_(m) C(O)(CH₂)_(m) R^(5a)), N((CH₂)_(q) Q(CH₂)_(m) R⁵), N(Q'(CH₂)_(m) R⁵), C(O)N((CH₂)_(m) Q'(CH₂)_(m) R^(5a)), C(O), C(O)CH₂, C(O)(CH₂)_(r) NR³ (CH₂)_(r), NR³ C(O), NR³ C(O)NR³, S(O)₂, SO₂ CH₂, SO₂ NR³, NR³ SO₂, and NR³ SO₂ NR³ ; B is selected from:X--Y, C₃₋₆ alkyl, benzyl substituted with 0-2 R⁶, C₅₋₆ carbocyclic group substituted with 0-2 R⁶, and 5-6 membered heterocyclic group containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ; X is selected from --C(O)--, --C(O)CR³ R^(3') --, --S(O)₂ --, --S(O)_(p) CR³ R^(3') --, --S(O)₂ NR³ --, --C(O)NR³ --, --NR³ --, --NR³ CR³ R^(3') --, and O; Y is selected from:C₅₋₆ carbocyclic group substituted with 0-2 R⁶, and 5-6 membered heterocyclic group containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁶ ; R⁶ is selected from H, OH, (CH₂)_(n) OR³, halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r) NR³ R^(3'), (CH₂)_(r) C(O)R³, NR³ C(O)R^(3'), NR³ C(O)NR³ R^(3'), SO₂ NR³ R^(3'), CONHSO₂ R⁴, NR³ SO₂ NR³ R^(3'), NR³ SO₂ --C₁₋₄ alkyl and (C₁₋₄ alkyl)-tetrazolyl; n is selected from 0, 1, and 2; and, r is selected from 0, 1, and
 2. 4. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 5. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt thereof.
 6. A method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 7. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt thereof. 